Brain stimulation system including diagnostic tool

ABSTRACT

A system for treating a patient comprises a stimulator for stimulating brain tissue, a controller for setting stimulation parameters and a diagnostic tool for measuring patient parameters and producing diagnostic data. The stimulation parameters comprise test stimulation parameters and treatment stimulation parameters. The stimulator delivers test stimulation energy to the brain tissue based on at least one test stimulation parameter and delivers treatment stimulation energy to the brain tissue based on at least one treatment stimulation parameter. One or more treatment stimulator parameters are determined based on the diagnostic data produced by the diagnostic tool The system is constructed and arranged to treat a neurological disease or a neurological disorder. Methods of treating a neurological disease or neurological disorder are also provided.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.14/917,917 (Attorney Docket No. 41551-709.301), filed Apr. 8, 2016, nowU.S. Pat. No. ______, which is a continuation of International PatentApplication No. PCT/IB2014/003188 (Attorney Docket No. 41551-709.601)filed Oct. 16, 2014, which claims priority under 35 USC 119(3) to U.S.Provisional Patent Application Ser. No. 61/893,023, entitled “BrainStimulation System including Diagnostic Tool”, filed Oct. 18, 2013, thecontents of which are incorporated herein by reference in theirentirety.

This application is related to: U.S. patent Ser. No. 11/303,293,entitled “Cognitive Function within a Human Brain”, filed Dec. 16, 2005;U.S. patent application Ser. No. 11/303,292, entitled “InducingNeurogenesis within a Human Brain”, filed Dec. 16, 2005; U.S. patentSer. No. 11/303,619, entitled “Regulation of Neurotrophins”, filed Dec.16, 2005; U.S. patent application Ser. No. 11/365,977, entitled “Methodof Treating Cognitive Disorders Using Neuromodulation”, filed Mar. 1,2006; and U.S. patent application Ser. No. 13/655,652, entitled “DeepBrain Stimulation of Memory Circuits in Alzheimer's Disease”, filed Oct.19, 2012; the contents of which are each incorporated herein byreference in their entirety.

FIELD OF INVENTION

The present invention relates generally to methods and systems fortreating a neurological disease or disorder, such as Alzheimer's Diseaseor other cognitive disorder. In particular, a system includes astimulation device and a diagnostic tool used to set one or moretreatment stimulation parameters used to treat a neurological disease ordisorder.

BACKGROUND OF THE INVENTION

Brain stimulation has been performed to treat numerous patient diseasesand disorders, such as neurological and psychiatric conditions. Bothinvasive and non-invasive technologies have been developed. Onenon-invasive system includes a transcranial magnetic stimulation devicethat directs a magnetic field from outside the patient's head to induceelectric currents in the patient's brain. Deep brain stimulation (DBS)can be accomplished using surgically implanted electrodes that deliverelectrical stimulation to precisely targeted areas in the brain. Morethan 60,000 patients have been implanted with deep brain electrodes, andits predominant application has been in the treatment of movementdisorders, most commonly Parkinson's disease.

There is a need for enhanced DBS and other brain stimulation systems,device and methods that result in increased safety and improved efficacyin the treatment of patients.

SUMMARY

According to an aspect of the present inventive concepts, a system fortreating a patient comprises a stimulator for stimulating brain tissue,a controller and at least one diagnostic tool. The system is constructedand arranged to treat at least one of a neurological disease or aneurological disorder. The controller is configured to set one or morestimulation parameters comprising at least one test stimulationparameter of the stimulator and at least one treatment stimulationparameter of the stimulator. The diagnostic tool is configured tomeasure at least one patient parameter and produce diagnostic datarepresenting the at least one measured patient parameter. The stimulatoris constructed and arranged to deliver test stimulation energy to thebrain tissue based on the at least one test stimulation parameter and todeliver treatment stimulation energy to the brain tissue based on the atleast one treatment stimulation parameter. The at least one treatmentstimulation parameter is determined based on the diagnostic data.

In some embodiments, the system is constructed and arranged to determinethe treatment stimulation parameter to at least one of prevent or reducean adverse event.

In some embodiments, the system is constructed and arranged to determinethe treatment stimulation parameter to improve the treatment of the atleast one of a neurological disease or a neurological disorder.

In some embodiments, the at least one treatment stimulation parametercomprises the at least one test stimulation parameter.

In some embodiments, the setting of the at least one treatmentstimulation parameter comprises at least one of setting an initialtreatment stimulation parameter or modifying an existing treatmentstimulation parameter.

In some embodiments, the stimulator is constructed and arranged tostimulate brain tissue with a first set of test stimulation parametersfor a first time period and a second set of test stimulation parametersfor a second time period, and the diagnostic data can comprise firstdiagnostic data associated with the first stimulation time period andsecond diagnostic data associated with the second time period. The atleast one treatment stimulation parameter can approximate the first setof test stimulation parameters or the second set of test stimulationparameters. The at least one treatment stimulation parameter can beassociated with a desired treatment of the at least one of aneurological disease or a neurological disorder. The at least onetreatment stimulation parameter can be associated with a desired memoryrecall by the patient. The at least one treatment stimulation parametercan be associated with at least one of prevention or reduction of anadverse event. The adverse event can comprise an event selected from thegroup consisting of: undesirable heart rate; undesirable respirationrate; undesirable sweating; undesirable hallucinations; undesirabletingling; flushing; undesirable psychiatric effect; undesirablecognitive effect; unpleasant generalized warming; undesirableperceptions described as déjà vu; seizure; synchronized neuronal firingpattern; undesired neural response time; undesired brain state;undesired theta phase; undesired p300 amplitude; and combinationsthereof. The first time period and the second time period can compriseapproximately the same length of time. At least one of the first timeperiod or the second time period can comprise a time period of less thanor equal to 24 hours, such as a time period of less than or equal to 6hours, 3 hours, 1 hour, 30 minutes, 15 minutes, 10 minutes, 5 minutes or2 minutes. The diagnostic tool can comprise a memory test device. Thememory test device can comprise a form for recording memory test data.The at least one treatment stimulation parameter can approximate the setof test stimulation parameters that resulted in a higher test score. Thediagnostic tool can comprise a diagnostic device. At least one of thefirst set of test stimulation parameters or the second set of teststimulation parameters can be determined based on diagnostic dataproduced by the diagnostic tool.

In some embodiments, at least one of the stimulation parameterscomprises an electrical stimulation parameter selected from the groupconsisting of: voltage level such as an average voltage level, root meansquare (rms) voltage level and/or a peak voltage level; current levelsuch as an average current level, rms current level and/or a peakcurrent level; power level such as an average power level, rms powerlevel and/or a peak power level; frequency of stimulation signal; seriesof frequencies of the stimulation signal; phase of stimulation signal;pulse width modulation ratio; signal pulse width; current density suchas current density applied to tissue; single electrode selected toreceive stimulation energy; set of electrodes selected to receivemonopolar and/or bipolar stimulation energy; and combinations thereof.

In some embodiments, the stimulator comprises a brain inserted leadcomprising multiple electrodes, and at least one of the stimulationparameters comprises a subset of electrodes that receive stimulatingenergy. The subset of electrodes can comprise a single electrode. Thesubset of electrodes can comprise a pair of electrodes.

In some embodiments, at least one of the stimulation parameterscomprises a signal voltage ranging between 0.1 Volts and 10.0 Volts. Theat least one stimulation parameter can comprise a signal voltage rangingbetween 1.0 Volts and 6.0 Volts, such as a voltage between 1.0 Volts and3.0 Volts. The at least one stimulation parameter can comprise a voltageof less than or equal to 9.0 Volts, such as a stimulation parametercomprising a voltage of less than or equal to 8.0 Volts, 7.0 Volts, 6.0Volts, 5.0 Volts, 4.0 Volts or 3.5 Volts.

In some embodiments, at least one of the stimulation parameterscomprises a signal frequency ranging between 2 Hz and 1000 Hz. The atleast one stimulation parameter can comprise a signal frequency ofapproximately 130 Hz.

In some embodiments, at least one test stimulation parameter comprises asignal pulse width ranging between 30 microseconds and 150 microseconds.The at least one test stimulation parameter can comprise a signal pulsewidth of approximately 90 microseconds.

In some embodiments, at least one of the stimulation parameterscomprises a light stimulation parameter selected from the groupconsisting of: power of light delivered to tissue; frequency of lightdelivered to tissue; a modulation parameter of light delivered totissue; and combinations thereof.

In some embodiments, at least one of the stimulation parameterscomprises a sound stimulation parameter selected from the groupconsisting of: amplitude of sound delivered to tissue; frequency ofsound delivered to tissue; a modulation parameter of sound delivered totissue; and combinations thereof.

In some embodiments, at least one of the stimulation parameterscomprises an agent delivery stimulation parameter selected from thegroup consisting of: mass of agent delivered to tissue; volume of agentdelivered to tissue; concentration of agent delivered to tissue;delivery rate of agent delivered to tissue; and combinations thereof.

In some embodiments, the controller is constructed and arranged to setat least one stimulation parameter based on a threshold at which anadverse event is detected by the diagnostic tool. The adverse event cancomprise an event selected from the group consisting of: undesirableheart rate; undesirable respiration rate; undesirable sweating;undesirable hallucinations; undesirable tingling; flushing; undesirablepsychiatric effect; undesirable cognitive effect; unpleasant generalizedwarming; undesirable perceptions described as déjà vu; seizure;synchronized neuronal firing pattern; undesired neural response time;undesired brain state; undesired theta phase; undesired p300 amplitude;and combinations thereof. The at least one stimulation parameter can beset using a safety margin, such as a safety margin of at least 10%, orat least 20%, 30%, 40% or 50%. The at least one stimulation parameterset based on the adverse event threshold can comprise the at least onetreatment stimulation parameter. The at least one stimulation parameterset based on the adverse event threshold can comprise the at least onetest stimulation parameter.

In some embodiments, the controller is constructed and arranged to setat least one stimulation parameter based on a threshold at which adesired event was detected by the diagnostic tool. The desired event cancomprise an event selected from the group consisting of: recall of adesired memory; achievement of desired memory learning; desired level ofneuronal activity; acceptable physiologic condition such as anacceptable heart rate or acceptable level of neuronal activity;experiential phenomena such as those described in epilepsy literature;and combinations thereof. The at least one stimulation parameter setbased on the desired event threshold can comprise the at least onetreatment stimulation parameter. The at least one stimulation parameterset based on the desired event threshold can comprise the at least onetest stimulation parameter.

In some embodiments, the system is constructed and arranged to provideopen loop stimulation.

In some embodiments, the system is constructed and arranged to provideclosed loop stimulation. The closed loop stimulation can be providedbased on the diagnostic data produced by the diagnostic tool. The systemcan further comprise a sensor for producing a signal, wherein the closedloop stimulation is provided based on the sensor signal.

In some embodiments, the measuring performed by the diagnostic toolcomprises a function selected from the group consisting of: recording;gathering; assessing; collecting; determining; processing; combining;and combinations thereof.

In some embodiments, the diagnostic tool is constructed and arranged todetect an adverse event. The adverse event can comprise an eventselected from the group consisting of: undesirable heart rate;undesirable respiration rate; undesirable sweating; undesirablehallucinations; undesirable tingling; flushing; undesirable psychiatriceffect; undesirable cognitive effect; unpleasant generalized warming;undesirable perceptions described as déjà vu; seizure; synchronizedneuronal firing pattern; undesired neural response time; undesired brainstate; undesired theta phase; undesired p300 amplitude; and combinationsthereof.

In some embodiments, the diagnostic tool comprises a device selectedfrom the group consisting of: heart rate monitor; EKG measurementdevice; oximeter; combined heart rate and oximeter device such as apulse oximeter; blood pressure measurement device; neuronal activitymeasurement device; EEG measurement device; evoked response potential(ERP) measurement device; neurochemical analysis device; memory testdevice; memory test form; respiration measurement device; sweatmeasurement device; skin conductivity measurement device; pH measurementdevice; body motion measurement device; imaging device; and combinationsthereof.

In some embodiments, the diagnostic tool comprises at least two devicesselected from the group consisting of: heart rate monitor; EKGmeasurement device; oximeter; combined heart rate and oximeter devicesuch as a pulse oximeter; blood pressure measurement device; neuronalactivity measurement device; EEG measurement device; evoked responsepotential (ERP) measurement device; neurochemical analysis device;memory test device; memory test form; respiration measurement device;sweat measurement device; skin conductivity measurement device; pHmeasurement device; body motion measurement device; imaging device; andcombinations thereof. The diagnostic tool can comprise at least a heartrate monitor and a blood pressure measurement device. The diagnostictool can be constructed and arranged to detect a patient issue. Thepatient issue can comprise an inaccurate representation made by thepatient detected by at least one of heart rate data or blood pressuredata.

In some embodiments, the diagnostic tool comprises an EKG measurementdevice. At least one stimulation parameter can be set based on detectionof undesired EKG activity by the diagnostic tool.

In some embodiments, the diagnostic tool comprises a neuronal activitymeasurement device. The neuronal activity measurement device can beconstructed and arranged to measure a neuronal parameter selected fromthe group consisting of: single neuron activity; local field potential;event related potentials; electroencephalogram readings;electrocorticogram readings; and combinations thereof. At least onestimulation parameter can be set based on the detection of a conditionselected from the group consisting of: seizure; synchronized neuronalfiring pattern; undesired neural response time; undesired brain state;undesired theta phase; undesired p300 amplitude; and combinationsthereof.

In some embodiments, the diagnostic tool comprises an ERP measurementdevice. At least one stimulation parameter can be set based on thedetection of undesired ERP activity by the diagnostic tool.

In some embodiments, the diagnostic tool comprises a blood pressuremeasurement device. At least one stimulation parameter can be set basedon the detection of an undesired blood pressure reading by thediagnostic tool.

In some embodiments, the diagnostic tool comprises a blood oxygenmeasurement device. At least one stimulation parameter can be set basedon the detection of an undesired blood oxygen reading by the diagnostictool.

In some embodiments, the diagnostic tool comprises a body motionmeasurement device. At least one stimulation parameter can be set basedon the detection of an undesired body motion detected by the diagnostictool. The undesired body motion can comprise a tremor.

In some embodiments, the diagnostic tool comprises a neurochemicalanalysis device. The neurochemical analysis device can be constructedand arranged to measure a patient parameter selected from the groupconsisting of: a neurotransmitter level; a pH concentration; an ionconcentration; a lactate level; cerebral blood flow; glucoseutilization; oxygen extraction; and combinations thereof. At least onestimulation parameter can be set based on the detection of at least oneof an undesired neurochemical activity or an undesired neurochemicallevel.

In some embodiments, the diagnostic tool comprises an imaging device.The stimulator can comprise multiple stimulating elements and at leastone stimulation parameter can comprise at least one stimulating elementselected to deliver stimulation energy. The stimulator can comprisemultiple stimulating electrodes and at least one stimulation parametercan comprise at least one stimulating electrode selected to deliverelectrical stimulation energy. The at least one stimulating electrodecan be selected based on its position relative to tissue to bestimulated. The tissue to be stimulated can comprise at least thefornix.

In some embodiments, the diagnostic tool comprises an algorithm foranalyzing a patient assessment.

In some embodiments, the diagnostic tool comprises a patient assessmentrecording tool. The patient assessment recording tool can comprise atool selected from the group consisting of: form; a paper form;electronic form; tablet; personal computer; database; and combinationsthereof. The patient assessment can comprise an assessment selected fromthe group consisting of: an assessment received verbally from thepatient; an assessment received in written form from the patient; anassessment made by a caregiver of the patient; and combinations thereof.The patient assessment can comprise an assessment of the patient stateselected from the group consisting of: depression; paranoia;schizophrenia; suicidality; suicide ideation; apathy; anxiety; mania;and combinations thereof.

In some embodiments, the diagnostic tool comprises a sensor constructedand arranged to sense, record or otherwise produce the diagnostic data.The sensor can comprise at least one sensing element selected from thegroup consisting of: neuronal activity sensor; EEG sensor; local fieldpotential sensor; neurochemical sensor; pH sensor; pressure sensor;blood pressure sensor; an optical sensor; blood gas sensor; blood oxygensensor; a magnetic sensor; a strain gauge; and combinations thereof. Thesensor can comprise an implanted sensor. The sensor can be furtherconstructed and arranged to stimulate brain tissue. The sensor cancomprise at least one electrode.

In some embodiments, at least a first portion of the stimulator isconstructed and arranged to be implanted in the patient and the systemcan be constructed and arranged to collect the diagnostic data afterimplantation of the stimulator first portion. The diagnostic data can becollected at least 5 minutes after implantation of the stimulator firstportion, such as at least 24 hours or at least two weeks afterimplantation of the stimulator first portion.

In some embodiments, the system further comprises a stimulationthreshold, and the at least one treatment stimulation parameter is setbased on the stimulation threshold. The at least one treatmentstimulation can be set using a safety margin.

In some embodiments, the system further comprises a stimulationthreshold, and the at least one treatment stimulation parameter ismodified based on the stimulation threshold. The at least one treatmentstimulation parameter can be modified using a safety margin.

In some embodiments, the at least one of a neurological disease ordisorder comprises a disease or disorder selected from the groupconsisting of: Alzheimer's Disease (AD) such as Mild or ModerateAlzheimer's Disease; probable Alzheimer's Disease; a genetic form ofAlzheimer's Disease; Mild Cognitive Impairment (MCI); hippocampal damagesuch as hippocampal damage due to Alzheimer's disease, anoxia, epilepsyor depression; neuronal loss; neuronal damage; chemotherapy inducedmemory impairment; epilepsy; a seizure disorder; dementia; amnesia; amemory disorder such a spatial memory disorder; cognitive impairmentassociated with Schizophrenia; Parkinson's Disease related cognitiveimpairment or dementia; and combinations thereof.

In some embodiments, the system is constructed and arranged to treat atleast one of: negative symptoms of schizophrenia; negative symptoms ofdepression; a condition of reversible impaired memory; or a condition ofreversible impaired cognition.

In some embodiments, the system is constructed and arranged to treat atleast one neurological disease and at least one neurological disorder.In some embodiments, the system is constructed and arranged to treatmultiple neurological diseases. In some embodiments, the system isconstructed and arranged to treat multiple neurological disorders. Insome embodiments, the system is constructed and arranged to regulate thelevel of one or more neurotrophic factors and/or neurotransmitters. Insome embodiments, the system is constructed and arranged to amelioratecognitive decline associated with dementia.

In some embodiments, the patient has reduced integrity of white mattertracts innervating limbic structures such as the fornix as determined byfractional anisotropy maps using diffusion tensor imaging. Theinnervated limbic structures can comprise at least the fornix.

In some embodiments, the system is constructed and arranged to achieveat least one of: treats memory impairment; improves memory function;treats cognitive function loss; reverses synaptic loss; improvescognitive function; reduces degradation of cognitive function; promotesneurogenesis in the hippocampus of the patient's brain; drivesneurotrophin expression; regulates one or more biomarkers related toAlzheimer's Disease such as amyloid-beta, tau, and/or phosphorylatedtau; regulates BDNF expression; increases neurotransmitter release suchas acetylcholine; or improves glucose utilization in the temporal lobe,the parietal lobe or both lobes of the patient's brain.

In some embodiments, the brain tissue stimulated comprises tissueselected from the group consisting of: fornix; entorhinal cortex;hippocampus; anterior thalamic nucleus; amygdala; mammillary bodies;parahippocampal cortex; temporal neocortex; septal nuclei; nucleusbasalis of Meynert; subcallosal or subgenual cingulate; ventral capsule;ventral striatum and combinations thereof. In some embodiments, thebrain tissue stimulated comprises brain tissue selected from the groupconsisting of: Papez Circuit; hippocampus; cingulate gyrus; fornix; amammilothalamic tract; amygdala; hypothalamus; mammillary bodies; septalnuclei; temporal neocortex; the medial forebrain bundle; anterior andmediodorsal nuclei of the thalamus; the diagonal band of the Broca;temporal stem and temporal white matter; brainstem; nucleus basalis ofMeynert; anterior thalamic nucleus; entorhinal cortex; rhinal cortex;periventricular zone; anterior thalamus; anterior insula; caudate;dorsal anterior cortex; dorsal cingulate; medial frontal cortex; nucleusaccumbens; orbital frontal cortex; parietal region; periaqueductal grayarea; posterior cingulate area; subcallosal area; subcallosal cingulate;subgenual cingulate; Brodmann area 10; Brodmann area 24; Brodmann area25; Brodmann area 11/Brodmann area 10; Brodmann area 24b; Brodmann area31; Brodmann area 32/Brodmann area 10; Brodmann area 32/Brodmann area11; Brodmann area 39; Brodmann area 46; Brodmann area 46/Brodmann area9; Brodmann area 47; Brodmann area 6; Brodmann area 9; ventral/medialprefrontal cortex area; ventral/medial white matter; dorsolateralprefrontal cortex; premotor cortex; ventrolateral prefrontal cortex;dorsal anterior cingulate caudate nucleus; frontal pole periaqueductalgray area; dorsolateral prefrontal area; subsingular cingulate;parahippocampal cortex; parahippocampal gyrus; ventral capsule; ventralstriatum; and combinations thereof. In some embodiments, the braintissue stimulated does not comprise tissue selected from the groupconsisting of: hippocampal tissue; optical tract tissue; andcombinations thereof. In some embodiments, the brain tissue stimulateddoes not comprise tissue selected from the group consisting of:posterior hypothalamic area; ventral tegmental area; lateralhypothalamic area; anterior hypothalamic nucleus; paraventricularnucleus; dorsal medial hypothalamic nucleus; ventromedial hypothalamicnucleus; arcuate nucleus; lateral tuberal nucleus; medial preopticnucleus; supraoptic nucleus; and combinations thereof.

In some embodiments, the stimulator comprises at least an implantedportion. The at least an implanted portion can comprise at least oneelectrode constructed and arranged to stimulate brain tissue. The atleast one electrode can comprise an electrode selected from the groupconsisting of: single component bipolar electrode; multiple unipolarelectrodes; stacked contact electrodes; discrete electrodes, anelectrode strip, a grid of electrodes; paddle electrode;high-density/high channel or lead count micro-electrodes; andcombinations thereof. The at least one electrode can comprise at leastone electrode positioned in brain tissue. The at least one electrode cancomprise at least one electrode positioned proximate the fornix. The atleast one electrode can comprise two electrodes constructed and arrangedto be placed bilaterally about the fornix. The at least one electrodecan comprise at least one electrode positioned in a location to causestimulation of the fornix. The at least one electrode can comprisemultiple electrodes. The at least one electrode can comprise anelectrode constructed and arranged for monopolar delivery of electricalenergy. The at least one electrode can comprise an electrode constructedand arranged for multipolar delivery of electrical energy. The at leastan implanted portion can comprise an implanted stimulation elementselected from the group consisting of: electrode such as one or moreelectrodes configured to deliver electrical stimulation energy; magneticfield delivery element; light delivery element such as a visible,ultraviolet or infrared light delivery element; optogenetic deliveryelement; sound delivery element such as a subsonic wave or ultrasoundwave delivery element; agent delivery element such as a chemical orpharmaceutical agent delivery element; and combinations thereof. Thesystem can further comprise an energy generating element constructed andarranged to deliver energy selected from the group consisting of:electromagnetic energy such as electrical energy and/or or magneticenergy; light energy such as visible, ultraviolet and/or infrared lightenergy; sound energy such as subsonic, sonic or ultrasound energy; andcombinations thereof. The at least an implanted portion can comprise animplanted signal generator.

In some embodiments, the stimulator comprises at least an externalportion. The at least an external portion can comprise an externalstimulation element. The external stimulation element can comprise anelectromagnetic field generator. The external stimulation element cancomprise a sound generator. The external stimulation element cancomprise a light energy generator. The at least an external portion cancomprise an electrical signal generator. The stimulator can furthercomprise an implanted stimulation element electrically connected to theelectrical signal generator. The implanted stimulation element cancomprise at least one electrode.

In some embodiments, the stimulator comprises an implanted portion andan external portion.

In some embodiments, the stimulator is constructed and arranged tostimulate tissue with electrical stimulation.

In some embodiments, the stimulator is constructed and arranged tostimulate tissue with a stimulation energy selected from the groupconsisting of: electrical stimulation; magnetic stimulation; opticalstimulation such as visible, ultraviolet or infrared light stimulation;sound stimulation such as ultrasound or subsonic wave stimulation;chemical stimulation such as stimulation from a drug or other agent; andcombinations thereof.

In some embodiments, the stimulator is constructed and arranged tostimulate the brain tissue in a continuous stimulation mode. In someembodiments, the stimulator is constructed and arranged to stimulate thebrain tissue in a cyclical stimulation mode.

In some embodiments, the stimulator is further constructed and arrangedto stimulate non-brain tissue. The non-brain tissue can comprisenon-brain nerve tissue. The non-brain tissue can comprise non-brainorgan tissue. The non-brain tissue can comprise tissue selected from thegroup consisting of: vagus nerve; trigeminal nerve; carotid sinus;spinal cord; dorsal root ganglia; tibial nerve; sacral nerve; gastricnerve; and combinations thereof.

In some embodiments, the stimulator comprises at least a portion of thediagnostic tool.

In some embodiments, the stimulator comprises at least one sensor.

In some embodiments, the controller is constructed and arranged totransmit information to the stimulator via wireless communication.

In some embodiments, the controller comprises at least a portion of thediagnostic tool.

In some embodiments, the controller comprises an algorithm for analyzingthe diagnostic data produced by the diagnostic tool. The algorithm canbe constructed and arranged to compare the diagnostic data to athreshold. The algorithm can be constructed and arranged to set the atleast one treatment stimulation parameter based on a safety margin.

According to another aspect of the present inventive concepts, a methodfor treating a patient comprises selecting a patient and providing astimulation system. The stimulation system comprises a stimulator; acontroller; and a diagnostic tool. The method further includes measuringat least one patient parameter with the diagnostic tool and producingdiagnostic data representing the at least one measured patientparameter; and setting a stimulation parameter of the system with thecontroller based on the diagnostic data. The method is constructed andarranged to treat at least one of a neurological disease or aneurological disorder.

In some embodiments, the system, stimulator, controller and/ordiagnostic tool are constructed and arranged as described hereabove.

In some embodiments, the method further comprises implanting at least aportion of the stimulator in the patient. The method can furthercomprise performing an MRI procedure prior to and/or during thestimulator implantation to produce at least one MRI image, wherein thestimulator comprises a stimulating element that is implanted relative toa fornix target identified on the at least one MRI image. Implanting thestimulator can comprise implanting one or more electrodes in a locationselected from the group consisting of: in the Papez Circuit of thepatient's brain; approximately 2 mm anterior and parallel to thevertical portion of the fornix; in the optic tract such that theventral-most contact is 2 mm above the dorsal surface of the optictract; approximately 5 mm from the midline; and combinations thereof.

In some embodiments, the stimulation parameter set comprises a treatmentstimulation parameter.

In some embodiments, the stimulation parameter set comprises a teststimulation parameter.

In some embodiments, the stimulation parameter is set using a safetymargin.

The technology described herein, along with the attributes and attendantadvantages thereof, will best be appreciated and understood in view ofthe following detailed description taken in conjunction with theaccompanying drawings in which representative embodiments are describedby way of example.

BRIEF DESCRIPTION OF THE DRAWINGS

The foregoing and other objects, features and advantages of embodimentsof the present inventive concepts will be apparent from the moreparticular description of preferred embodiments, as illustrated in theaccompanying drawings in which like reference characters refer to thesame or like elements. The drawings are not necessarily to scale,emphasis instead being placed upon illustrating the principles of thepreferred embodiments.

FIG. 1 illustrates a schematic view of a system for stimulating one ormore portions of a patient's brain, consistent with the presentinventive concepts.

FIG. 2 illustrates a flow chart of a method for treating a patient witha brain stimulation system, consistent with the present inventiveconcepts.

FIG. 3 illustrates a flow chart of a series of steps for performing thediagnostic test of FIG. 2, consistent with the present inventiveconcepts.

FIG. 4 illustrates a schematic of an electrical brain stimulator,consistent with the present inventive concepts.

DETAILED DESCRIPTION OF THE DRAWINGS

The terminology used herein is for the purpose of describing particularembodiments and is not intended to be limiting of the inventiveconcepts. As used herein, the singular forms “a,” “an” and “the” areintended to include the plural forms as well, unless the context clearlyindicates otherwise.

It will be further understood that the words “comprising” (and any formof comprising, such as “comprise” and “comprises”), “having” (and anyform of having, such as “have” and “has”), “including” (and any form ofincluding, such as “includes” and “include”) or “containing” (and anyform of containing, such as “contains” and “contain”) when used herein,specify the presence of stated features, integers, steps, operations,elements, and/or components, but do not preclude the presence oraddition of one or more other features, integers, steps, operations,elements, components, and/or groups thereof.

It will be understood that, although the terms first, second, third etc.may be used herein to describe various limitations, elements,components, regions, layers and/or sections, these limitations,elements, components, regions, layers and/or sections should not belimited by these terms. These terms are only used to distinguish onelimitation, element, component, region, layer or section from anotherlimitation, element, component, region, layer or section. Thus, a firstlimitation, element, component, region, layer or section discussed belowcould be termed a second limitation, element, component, region, layeror section without departing from the teachings of the presentapplication.

It will be further understood that when an element is referred to asbeing “on”, “attached”, “connected” or “coupled” to another element, itcan be directly on or above, or connected or coupled to, the otherelement or intervening elements can be present. In contrast, when anelement is referred to as being “directly on”, “directly attached”,“directly connected” or “directly coupled” to another element, there areno intervening elements present. Other words used to describe therelationship between elements should be interpreted in a like fashion(e.g., “between” versus “directly between,” “adjacent” versus “directlyadjacent,” etc.).

Spatially relative terms, such as “beneath,” “below,” “lower,” “above,”“upper” and the like may be used to describe an element and/or feature'srelationship to another element(s) and/or feature(s) as, for example,illustrated in the figures. It will be understood that the spatiallyrelative terms are intended to encompass different orientations of thedevice in use and/or operation in addition to the orientation depictedin the figures. For example, if the device in a figure is turned over,elements described as “below” and/or “beneath” other elements orfeatures would then be oriented “above” the other elements or features.The device can be otherwise oriented (e.g., rotated 90 degrees or atother orientations) and the spatially relative descriptors used hereininterpreted accordingly.

The term “and/or” where used herein is to be taken as specificdisclosure of each of the two specified features or components with orwithout the other. For example “A and/or B” is to be taken as specificdisclosure of each of (i) A, (ii) B and (iii) A and B, just as if eachis set out individually herein.

It is appreciated that certain features of the invention, which are, forclarity, described in the context of separate embodiments, may also beprovided in combination in a single embodiment. Conversely, variousfeatures of the invention which are, for brevity, described in thecontext of a single embodiment, may also be provided separately or inany suitable sub-combination.

For example, it will be appreciated that all features set out in any ofthe claims (whether independent or dependent) can be combined in anygiven way.

The systems, devices and methods of the present inventive concepts areapplicable to treat a patient, such as to treat one or more cognitivedisorders of a patient. The cognitive disorders include but are notlimited to: Alzheimer's Disease (AD) such as Mild or ModerateAlzheimer's Disease; probable Alzheimer's Disease; a genetic form ofAlzheimer's Disease; Mild Cognitive Impairment (MCI); hippocampal damagesuch as hippocampal damage due to Alzheimer's disease, anoxia, epilepsyor depression; neuronal loss; neuronal damage; chemotherapy inducedmemory impairment; epilepsy; a seizure disorder; dementia; amnesia; amemory disorder such a spatial memory disorder; cognitive impairmentassociated with Schizophrenia; Parkinson's Disease related cognitiveimpairment or dementia; and combinations of these. Additionally oralternatively, the patient can be selected to treat negative symptoms ofa disease or disorder selected from the group consisting of:schizophrenia; depression; other conditions of reversible impairedmemory or cognition; and combinations of these.

In some embodiments, the patient is selected for treatment as describedin applicant's co-pending U.S. application Ser. No. 13/655,652, entitled“Deep Brain Stimulation of Memory Circuits in Alzheimer's Disease”,filed Oct. 19, 2012, the contents of which is incorporated herein byreference in its entirety.

As used herein, the term “wired pathway” shall refer to an energy and/orinformation transmission pathway including a physical conduit such as aflexible conduit comprising: one or more wires; one or more optical(e.g. light transmitting) fibers; one or more fluid delivery tubes; andcombinations of these.

As used herein, the term “wireless” or “wireless pathway” shall refer toan energy and/or information transmission pathway that does not includeor otherwise rely on a physical conduit for transmission, such as anelectromagnetic or light transmission of energy and/or information thatpasses through the tissue of a patient without the use of a physicalconduit.

Referring now to FIG. 1, a system for stimulating a patient's brain isillustrated, consistent with the present inventive concepts. System 10includes stimulator 100, controller 200 and diagnostic tool 300. System10 can be constructed and arranged to treat a neurological disease, aneurological disorder and/or another patient disease or disorder, asdescribed in detail herebelow. Stimulator 100 is configured to stimulatetissue, such as to stimulate at least a portion of patient P's brain B,such as via pathway 40. Controller 200 is configured to initiate and/oradjust (hereinafter “set” or “setting”) one or more stimulationparameters of stimulator 100, such as one or more test stimulationparameters 106 and/or one or more treatment stimulation parameters 107(collectively or singly referred to as “stimulation parameters” 105),also as described in detail herebelow. Diagnostic tool 300 isconstructed and arranged to measure one or more patient parameters, andto produce diagnostic data 305 representing the measured patientparameters. The measuring of diagnostic data 305 by diagnostic tool 300can include but is not limited to performing a data measurement functionselected from the group consisting of: recording; gathering; assessing;collecting; determining; processing; combining; and combinations ofthese.

In some embodiments, system 10 is constructed and arranged to treat aneurological disease and/or disorder selected from the group consistingof: probable Alzheimer's Disease; a genetic form of Alzheimer's Disease;Mild Cognitive Impairment; hippocampal damage such as hippocampal damagedue to Alzheimer's Disease, anoxia, epilepsy or depression; dementia;amnesia; a memory disorder such as a spatial memory disorder; cognitiveimpairment associated with Schizophrenia; Parkinson's Disease relatedcognitive impairment or dementia; neuronal loss; neuronal damage;chemotherapy induced memory impairment; epilepsy; seizure disorder; andcombinations of these. In some embodiments, system 10 is constructed andarranged to treat multiple neurological diseases, multiple neurologicaldisorders and/or at least one neurological disease and at least oneneurological disorder.

System 10 can be constructed and arranged such that stimulator 100delivers test stimulation energy to brain B based on one or more teststimulation parameters 106. System 10 can be further constructed andarranged to deliver treatment stimulation energy to brain B based on oneor more treatment stimulation parameters 107, such as when the treatmentstimulation parameters 107 are based on the diagnostic data 305 producedby diagnostic tool 300. In some embodiments, stimulator 100 isconstructed and arranged as is described in reference to stimulator 100of FIG. 4 described herebelow. In some embodiments, system 10 is used asis described in reference to the method of FIG. 2 herebelow.

Pathway 40 can comprise a wired or wireless pathway as described indetail herein. Stimulator 100 can comprise an implantable stimulator, anexternal (e.g. non-implanted) stimulator, or it can comprise bothimplantable and external portions. Controller 200 is configured tocommunicate with stimulator 100, via pathway 20, such as to set one ormore stimulation parameters 105 of stimulator 100. Pathway 20 cancomprise a wired or wireless pathway as described herein. Stimulator 100can comprise a user interface 101, such as a user interface 101positioned on an external portion of stimulator 100. In someembodiments, system 10 is constructed and arranged such thatcommunication (e.g. wired or wireless communication) can occur betweencontroller 200 and diagnostic tool 300, such as to transfer diagnosticdata 305 and/or one or more stimulation parameters 105.

One or more components of system 10 can include another component ofsystem 10, such as when one or more of at least a portion of stimulator100, controller 200 and diagnostic tool 300 are combined (e.g. within acommon housing). For example, at least a portion of stimulator 100 cancomprise at least a portion of controller 200, such as when stimulator100 includes an external portion comprising user interface 101 which isconfigured to set one or more stimulation parameters 105. In someembodiments, at least a portion of stimulator 100 can comprise at leasta portion of diagnostic tool 300, such as when stimulator 100 comprisesone or more sensors 430 constructed and arranged to record one or morepatient parameters, such as are described in detail herebelow. In someembodiments, one or more sensors 430 are further constructed andarranged to stimulate tissue such as brain tissue. In some embodiments,at least a portion of controller 200 comprises at least a portion ofdiagnostic tool 300, such as when controller 200 comprises one or moresensors 230 (also as described in detail herebelow) constructed andarranged such that controller 200 can function as a heart rate monitor,a blood pressure monitor and/or other diagnostic tool configured toproduce diagnostic data 305.

Diagnostic tool 300 is constructed and arranged to record, gather,assess, collect, determine and/or otherwise measure one or more patientparameters and produce diagnostic data 305 representing these one ormore patient parameters. Diagnostic tool 300 can be further constructedand arranged to process (e.g. mathematically process) and/or combinemeasured data, such as when diagnostic tool 300 comprises one or morealgorithms configured to analyze diagnostic data 305, such as one ormore algorithms that compare diagnostic data 305 to one or more“stimulation thresholds” (as described herebelow) and record one or morestimulation parameters associated with the one or more stimulationthresholds. In some embodiments, an algorithm is constructed andarranged to determine a stimulation threshold correlating to anundesired clinical event or other undesired patient event (hereinafter“adverse event”) as described herein. In some embodiments, an algorithmis constructed and arranged to determine a stimulation thresholdcorrelating to a desired clinical event or other desired patent event(hereinafter “desired event”), such as an event in which a desiredmemory recall occurs, a desired memory learning is achieved and/or otherdesired event takes place, as described herebelow.

System 10 (e.g. automatically or semi-automatically) and/or an operatorof system 10 can use the diagnostic data 305 to set and/or modify thestimulation provided by stimulator 100. Setting of one or more treatmentstimulation parameters 107 using or otherwise based on diagnostic data305 can be performed to improve therapy achieved by system 10, asdescribed in detail herebelow. Alternatively or additionally, setting ofone or more treatment stimulation parameters 107 using or otherwisebased on diagnostic data 305 can be performed to at least one of reduceand/or prevent (hereinafter “reduce”) an adverse event for patient P,also as is described in detail herebelow. Diagnostic data 305 can beused to determine if an adverse event has occurred or is about to occur.Alternatively or additionally, diagnostic data 305 can be used todetermine if a desired event has occurred or is about to occur. In eachof these instances, the test stimulation parameters 106 causing theadverse event or desired event represent a stimulation threshold forthat particular event.

In some embodiments, a treatment stimulation parameter 107 is set at alevel below or otherwise away from (hereinafter “below”) the stimulationthreshold that caused an adverse event (e.g. as determined in adiagnostic test of the present inventive concepts). In theseembodiments, the term “below” does not necessarily correlate to a lowermagnitude of stimulation energy, but represents a lower, greater ordifferent value that tends toward avoiding occurrence of the adverseevent. For example, if flow rates of 5ml/hr or less of an agent infusedby an external stimulation element 150 a (e.g. via a catheter) or animplanted stimulation element 150 b, each described herebelow, caused anadverse event, treatment stimulation parameter 107 could be set to alevel of more than 5ml/hr to avoid the adverse event. In someembodiments, a treatment stimulation parameter 107 is set at a safetymargin below the stimulation threshold (e.g. a voltage or current levelthat is less than the level causing the adverse event). In someembodiments, an approximate 50% safety margin is used (e.g. a voltage orcurrent is set to approximately half the voltage or current causing theadverse event). In other embodiments, a safety margin of at least 10% isused, such as a safety margin of at least 20%, 30%, 40% or 50%.

In some embodiments, a treatment stimulation parameter 107 is set at alevel at or above (hereinafter “above”) a stimulation threshold thatcaused a desired event (e.g. as determined in a diagnostic test of thepresent inventive concepts). In these embodiments, the term “above” doesnot necessarily correlate to a higher magnitude of stimulation energy,but represents a higher, lower or similar value that tends towardcausing occurrence of the desired event.

Stimulator 100 can comprise stimulation element 150 a, which isconfigured to generate and/or deliver energy to stimulate brain B orother tissue of patient P. In some embodiments, stimulator 100 furthercomprises stimulation element 150 b, which can also be configured togenerate and/or deliver energy to stimulate brain B or other tissue ofthe patient. Stimulation elements 150 a and/or 150 b, collectively orsingly referred to as “stimulation element 150”, can comprise astimulation delivery element configured to deliver stimulation energyand/or to otherwise stimulate one or more portions of brain B or othertissue of patient P. Alternatively or additionally, stimulation element150 can comprise a stimulation energy generating element configured toproduce energy to stimulate tissue. In some embodiments, stimulationelement 150 a comprises a stimulation generating element that deliversenergy to stimulation element 150 b configured as a stimulation deliveryelement, such as when stimulation element 150 b comprises one or moreelectrodes which receive electrical energy from stimulation element 150a.

In some embodiments, a stimulation element 150 comprises one or morestimulation delivery elements selected from the group consisting of:electrode such as one or more electrodes configured to deliverelectrical stimulation energy; magnetic field delivery element; lightdelivery element such as a visible, ultraviolet or infrared lightdelivery element; optogenetic delivery element; sound delivery elementsuch as a subsonic wave or ultrasound wave delivery element; agentdelivery element such as a chemical or pharmaceutical agent deliveryelement; and combinations of these. Alternatively or additionally,stimulation element 150 can comprise one or more stimulation generatingelements constructed and arranged to deliver a form of energy selectedfrom the group consisting of: electromagnetic energy such as electricalenergy and/or magnetic energy; light energy such as visible, ultravioletand/or infrared light energy; sound energy such as subsonic, sonic orultrasound energy; and combinations of these. Alternatively oradditionally, stimulation element 150 can comprise an agent deliverypump or reservoir; such as a pump configured to deliver a chemical orpharmaceutical agent through one or more catheters or other fluiddelivery conduits.

Stimulator 100 can comprise one or more implanted components (e.g. oneor more discrete or otherwise physically separated components), one ormore components external to the patient P's body, or both at least oneimplanted component and at least one external component. Stimulator 100can comprise two or more components, such as two or more componentsconnected with a physical cable including electrically conductive wiresand/or optical fibers, or two or more components which transmit and/orreceive information via wireless transmission. In some embodiments,stimulator 100 and/or its implanted housing 110 (described herebelow)are configured as is described in applicant's co-pending U.S. patentapplication Ser. No. 13/655,652, entitled “Deep Brain Stimulation ofMemory Circuits in Alzheimer's Disease”, filed Oct. 19, 2012, thecontents of which is incorporated herein by reference in its entirety.

Stimulator 100 can comprise at least one housing, such as housing 110.Housing 110 can surround electronic components, a power supply such as abattery, stimulation element 150 a, and other components such as thosedescribed in reference to FIG. 4 herebelow. Housing 110 can beconstructed and arranged for implantation in the patient or remainexternal.

In some embodiments, stimulator 100 comprises at least an implantedportion and stimulation element 150 a (positioned within the implantedportion) comprises a signal generator, such as a signal generatorconstructed and arranged to deliver electrical and/or one or more otherforms of energy to stimulation element 150 b. In these embodiments,energy generated by stimulation element 150 a can travel through a wiredor wireless pathway 40 (e.g. a pathway that comprises one or more wiresor other energy carrying conduits which pass under the skin from thechest to the brain) to deliver stimulating energy to one or morestimulation elements 150 b. Stimulation elements 150 b can be positionedon, in and/or proximate patient P's brain B and/or other tissue to bestimulated. In some embodiments, one or more stimulation elements 150 bcan be positioned in a location selected from the group consisting of: asubdural location; a supradural location; on and/or in the skull; onand/or in the scalp; and combinations of these.

In some embodiments, stimulator 100 comprises at least an externalportion and stimulation element 150 a is positioned in an externalportion of stimulator 100. In these embodiments, an externallypositioned stimulation element 150 a can be configured to non-invasivelydeliver energy to tissue. For example, stimulation element 150 a cancomprise an electromagnetic field generator, a sound generator, a lightenergy generator, or other energy generator configured to deliver energynon-invasively through the skin through a wireless pathway 40 (e.g.through the skin and skull of patient P) to stimulate one or moreportions of brain B. Wireless stimulation transmissions can comprise atransmission selected from the group consisting of: electromagneticwaves; sound waves such as ultrasonic and subsonic waves; light waves;and combinations of these. Non-limiting examples of non-invasivestimulation devices include: one or more transcranial magneticstimulation devices, such as is described in U.S. Pat. No. 7,087,008,entitled “Apparatus and Methods for Delivery of Transcranial MagneticStimulation”, filed May 3, 2002, the contents of which is incorporatedherein by reference in its entirety; one or more external focused energydelivery devices, such as is described in U.S. patent application Ser.No. 13/169,288, entitled “Systems and Methods for Stimulating TissueUsing Focused Energy”, filed Jun. 27, 2011, the contents of which isincorporated herein by reference in its entirety; ultrasound stimulationdevices; optogenetics-based stimulation devices; light-based stimulationdevices; fiber optic based stimulation devices; and combinations ofthese.

Pathway 40 can comprise one or more physical conduits such as wires,fluid delivery tubes, and/or optical fibers that connect to one or moreelectrodes, agent delivery elements and/or other stimulation deliveryelements 150 b positioned in and/or proximate to a location within brainB or other tissue to be stimulated. Pathway 40 can include a first leadthat is positioned to stimulate a specific site in brain B. In theseembodiments, stimulation elements 150 b can comprise one or moreelectrodes positioned in the hypothalamic area in proximity to thefornix, and/or at a different location as described herebelow.Stimulator 100 can take the form of a fully implanted signal generator,such as a signal generator similar to signal generator Model 7424,manufactured by Medtronic, Inc. under the trademark Itrel II. Pathway 40can comprise one or more forms, such as any of the leads compatible withthe Model 7424 such as Model 3387 lead set, for stimulating brain B. Thelead can be coupled to stimulator 100 by a compatible lead extension.

Controller 200 can be configured to initiate, adjust and/or otherwiseset at least one test stimulation parameter 106 and/or treatmentstimulation parameter 107, such as a stimulation parameter selected fromthe group consisting of: voltage level such as an average voltage level,rms voltage level and/or a peak voltage level; current level such as anaverage current level, rms current level and/or a peak current level;power level such as an average power level, rms power level and/or apeak power level; frequency of stimulation signal; series of frequenciesof the stimulation signal; phase of stimulation signal; pulse widthmodulation ratio; signal pulse width; current density such as currentdensity applied to tissue; single electrode selected to receivestimulation energy; set of electrodes selected to receive monopolarand/or bipolar stimulation energy; agent delivery rate; physiologicconcentration; power of light delivered to tissue; frequency of lightdelivered to tissue; a modulation parameter of light delivered totissue; amplitude of sound delivered to tissue; frequency of sounddelivered to tissue; a modulation parameter of sound delivered totissue; mass of agent delivered to tissue; volume of agent delivered totissue; concentration of agent delivered to tissue; delivery rate ofagent delivered to tissue; and combinations of these. System 10 teststimulation parameters 106 and/or treatment stimulation parameters 107can be set by signals sent from controller 200 to stimulator 100 viapathway 20.

In some embodiments, stimulation element 150 b comprises up to fourimplanted stimulation electrodes, such as four electrodes implanted intoa portion of brain B using conventional stereotactic surgicaltechniques. In some embodiments, stimulation element 150 b comprises twoor more electrodes spaced approximately 1.5 mm apart. Each of the up tofour electrodes (stimulation elements 150 b) can be individuallyconnected to stimulator 100 through pathway 40 including a first leadwith at least one conductor. The first lead can be surgically implantedthrough a hole in the skull and the at least one conductor can beimplanted between the skull and the scalp. The lead with the one or moreconductors can be electrically attached to stimulator 100. In someembodiments, at least a portion of stimulator 100 is implanted in ahuman body, for example in the chest, within an arm, and/or in theabdomen of a human body. In some embodiments, at least a portion ofstimulator 100 is implanted in the chest and pathway 40 comprises one ormore conductors that are implanted subcutaneously along the head, neckand shoulder to connect a housing of the portion of stimulator 100implanted in the chest. Pathway 40 can comprise twin leads, a first leadand a second lead (e.g. each including one or more conductors), that areconnected to a first electrode (e.g. one or more electrodes) and asecond electrode (e.g. one or more electrodes), respectively, the twoleads implanted into brain B bilaterally (e.g. bilaterally about thefornix of brain B), with each lead connected to a single stimulator 100portion. Alternatively, the second lead and second electrode can besupplied with stimulating pulses from a separate stimulator 100 portion(e.g. a second portion implanted in the chest or other internal locationof the patient P). In some embodiments, first and second leads are alsoattached (e.g. on the opposite end) to a stimulation element 150 bcomprising two or more electrodes, such as two electrodes positioned intwo separate nuclei that potentiate each other's effects. In someembodiments, the first and second leads are attached to a stimulationelement 150 b comprising two electrodes in two separate nuclei withopposite effects, with the dual stimulation delivered being used tofine-tune the response through opposing forces. It will be appreciated,however, that any number of electrodes or other stimulation elements 150a and/or 150 b can be positioned within brain B, on or proximate tobrain B, remote from brain B, and/or external to the patient P's body,in accordance with the present inventive concepts. Additionally, one ormore secondary electrodes or secondary stimulation elements can beimplanted or otherwise positioned so that a secondary stimulationportion lies in communication with another predetermined portion of abrain.

System 10 can be utilized in monopolar and/or multipolar electricalstimulation configurations (e.g. monopolar, bipolar and/or stimulationconfigurations including 3 or more poles). In some embodiments, system10 delivers monopolar energy, such as when housing 110 and at least aportion of stimulator 100 are implanted in the patient, such thathousing 110 can function as a lead (e.g. a positive lead). In theseembodiments, stimulation element 150 b can comprise one or moreelectrodes positioned in brain B, the one or more electrodes functioningas the associated lead (e.g. as negative leads).

System 10 can be constructed and arranged to provide stimulationcontinuously and/or intermittently, such as for a chronic period of timeof at least 1 month, at least 3 months or at least 6 months. In somecases, stimulation can be provided for a longer period of time such as12 months or more. Intermittent stimulation can include delivery ofconstant or pulsed stimulation energy with stimulation “on” times of atleast 30 minutes, or at least 60 minutes. In some embodiments, theconstant or pulsed stimulation energy delivery duty cycle (ratio of “on”time to the sum of “on” time plus “off” time) ranges from 20% to 80%.Stimulation can be performed in either an open loop mode or a closedloop mode. In some embodiments, stimulation is initiated and/or modifiedto achieve an acute goal (e.g. by a caregiver or the patient), such asto perform an acute task or activity in which enhanced memory functionis desirable. Stimulation can comprise delivery of electrical energy,sound energy, chemical energy, light energy, and/or the delivery of apharmaceutical drug or other agent. Stimulation elements 150 a and/or150 b configured as electrodes can be of various forms selected from thegroup consisting of: single component bipolar electrode; multipleunipolar electrodes; stacked contact electrodes; discrete electrodes;electrode strip; grid of electrodes; paddle electrode; high-density/highchannel or lead count micro-electrodes; and combinations of these.

Stimulator 100 can include an agent delivery mechanism, such as amechanism including a pump and one or more catheters configured todeliver one or more agents to one or more brain or other body locations.In some embodiments, system 10 is constructed and arranged to deliverboth electrical stimulation and agent delivery, sequentially and/orsimultaneously. In these embodiments, a pump can be implanted below theskin of patient P, such as when the pump has an access port into which aneedle can be inserted through the skin to inject a quantity of a liquidagent, such as a medication or other drug. The liquid agent is deliveredfrom the pump through a catheter (e.g. after traveling from a pumpingchamber and through a catheter access port attached to the side of thepump), and into patient P. The catheter can be positioned to deliver theagent to one or more specific infusion sites of brain B. The pump cantake the form of any number of known implantable pumps including forexample that which is disclosed in U.S. Pat. No. 4,692,147, “DrugAdministration Device”, the contents of which is incorporated herein byreference in its entirety. The distal end of the catheter can terminatein a cylindrical hollow tube having a distal end implanted, such as byconventional stereotactic surgical techniques, into a portion of brain Bto affect tissue within brain B. The tube can be surgically implantedthrough a hole in the skull and the catheter can be implanted betweenthe skull and the scalp, with the catheter fluidly attached to the pump.The pump can be implanted in a subcutaneous pocket located in the chestbelow the clavicle. Alternatively, the pump can be implanted in theabdomen. The catheter can include twin tubes (e.g. two separatecatheters attached to a single pump or a single catheter with twolumens) that have their distal portions implanted into brain B inbilateral locations. Alternatively, a second catheter can be implanted,for example on the other side of brain B, and can be supplied with drugsor other stimulating agents from a separate pump. The one or more pumpscan be programmed to deliver one or more agents according to aparticular dosage and/or time interval. For example, a pump can deliverdrug therapy over a first period with a high dose configured to induce ahigh level of neurogenesis, after which a lower dose is delivered tomaintain neurogenesis and secondary trophic effects (e.g. axonalsprouting and synaptogenesis). Any number of neurotrophins or drugs thatstimulate neurons can be administered including, but not limited to:NGF; BDNF; NT-3; FGF; EGF; GDNF; Neurteurin; Artemin; Persephin; andcombinations of these.

System 10 can be constructed and arranged to modulate memory circuits toproduce clinical benefits, such as to modulate memory circuits in thebrain B of patient P to reduce the progression of or otherwise treat theeffects of Alzheimer's Disease (AD). System 10 can modulate memorycircuits in brain B via electrical or other stimulation means. System 10can be constructed and arranged to stimulate brain B tissue selectedfrom the group consisting of: fornix; entorhinal cortex; hippocampus;anterior thalamic nucleus; amygdala; mammillary bodies; parahippocampalcortex; temporal neocortex; septal nuclei; nucleus basalis of Meynert;subcallosal or subgenual cingulate; ventral capsule; ventral striatum;and combinations thereof. In some embodiments, the brain tissuestimulated comprises brain tissue selected from the group consisting of:Papez Circuit; hippocampus; cingulate gyrus; fornix; a mammilothalamictract; amygdala; hypothalamus; mammillary bodies; septal nuclei;temporal neocortex; the medial forebrain bundle; anterior andmediodorsal nuclei of the thalamus; the diagonal band of the Broca;temporal stem and temporal white matter; brainstem; nucleus basalis ofMeynert; anterior thalamic nucleus; entorhinal cortex; rhinal cortex;periventricular zone; anterior thalamus; anterior insula; caudate;dorsal anterior cortex; dorsal cingulate; medial frontal cortex; nucleusaccumbens; orbital frontal cortex; parietal region; periaqueductal grayarea; posterior cingulate area; subcallosal area; subcallosal cingulate;subgenual cingulate; Brodmann area 10; Brodmann area 24; Brodmann area25; Brodmann area 11/Brodmann area 10; Brodmann area 24b; Brodmann area31; Brodmann area 32/Brodmann area 10; Brodmann area 32/Brodmann area11; Brodmann area 39; Brodmann area 46; Brodmann area 46/Brodmann area9; Brodmann area 47; Brodmann area 6; Brodmann area 9; ventral/medialprefrontal cortex area; ventral/medial white matter; dorsolateralprefrontal cortex; premotor cortex; ventrolateral prefrontal cortex;dorsal anterior cingulate caudate nucleus; frontal pole periaqueductalgray area; dorsolateral prefrontal area; subsingular cingulate;parahippocampal cortex; parahippocampal gyrus; ventral capsule; ventralstriatum; and combinations thereof. In some embodiments, the braintissue stimulated does not comprise tissue selected from the groupconsisting of: hippocampal tissue; optical tract tissue; andcombinations thereof. In some embodiments, the brain tissue stimulateddoes not comprise tissue selected from the group consisting of:posterior hypothalamic area; ventral tegmental area; lateralhypothalamic area; anterior hypothalamic nucleus; paraventricularnucleus; dorsal medial hypothalamic nucleus; ventromedial hypothalamicnucleus; arcuate nucleus; lateral tuberal nucleus; medial preopticnucleus; supraoptic nucleus; and combinations thereof. The stimulationsite within one or more locations of brain B tissue can be used tostimulate, activate or otherwise affect one or more similar or differentbrain B tissue locations, such as a stimulation configured to affect abrain B location selected from the group consisting of: fornix;hippocampus; parahippocampal gyrus; entorhinal cortex; amygdale;mammillary bodies; parahippocampal cortex; temporal neocortex; septalnuclei; nucleus basalis of Meynert; subcallosal or subgenual cingulate;and combinations of these. Alternatively or additionally, system 10 andone or more stimulation elements 150 can be constructed and arranged tostimulate non-brain tissue, such as nerve or organ tissue separate fromthe brain. Stimulated tissue can comprise tissue selected from the groupconsisting of: vagus nerve; trigeminal nerve; carotid sinus; spinalcord; dorsal root ganglia; tibial nerve; sacral nerve; gastric nerve;and combinations thereof. In some embodiments, system 10 is constructedand arranged to stimulate at least a portion of the hypothalamus, suchas at least a portion of the fornix. The fornix is a large axonal bundlethat constitutes a major inflow and output pathway from the hippocampusand medial temporal lobe. The hippocampus is a critical component of thelimbic circuitry and is distinguished among some of the regions of thebrain by persistent production of new neurons. The fornix is involved inmemory formation and is known to be affected early in the progression ofAD. In some embodiments, loss of fornix integrity associated withhippocampal volume loss can be detected by diagnostic tool 300 and usedby system 10 to predict the progression of AD.

System 10 can be constructed and arranged to sustain and/or improve thefunction of the fornix. Alternatively or additionally, system 10 can beconstructed and arranged to therapeutically affect the hippocampusand/or cortical circuits (e.g. the cortico-cortico circuits).Stimulation of the fornix by system 10 can be used to activate thehippocampus and cortical regions in brain B's default network, a networkof brain regions that are active when the individual is not focused onthe outside world and/or the brain is at wakeful rest. Patients with ADcan exhibit a decrease in glucose metabolism over time. System 10 can beconstructed and arranged to increase or maintain (e.g. prevent thedecrease of) glucose metabolism, such as by stimulating at least thefornix. System 10 can be constructed and arranged to increase ormaintain (e.g. prevent the decrease of) one or more portions ofhippocampal volume, such as by stimulating the fornix or other brain Blocation as described hereabove. In some embodiments, the stimulation ofsystem 10 results in neurogenesis, such as hippocampal neurogenesis.

System 10 can be constructed and arranged to produce clinical benefitsto patient P by modulating neurophysiologic activity in pathologicalcircuits. The pathological circuits can be causing functional impairmentin the neural elements and circuits underlying cognitive and/or memoryfunctions, and the stimulation provided by system 10 can improveclinical and/or neurobiological outcomes that result from thesepathological circuits. Stimulation provided by system 10 can be used tomodulate dysfunctional networks, such as to therapeutically manipulatethe levels of one or more deleterious proteins.

System 10 can be constructed and arranged to drive activity inprojection structures downstream from the stimulation site (e.g.downstream from the fornix). System 10 can be constructed and arrangedto provide evoked responses that are unequivocal and/or consistent.Stimulation received by system 10 can activate the cingulated gyrus andprecuneus area of the parietal lobe, including direct and trans-synapticsequential activation of downstream targets related to the connectivityof the fornix and hippocampus.

System 10 can be constructed and arranged to regulate the level of oneor more neurotrophic factors and/or neurotransmitters. System 10 can beconstructed and arranged to ameliorate cognitive decline associated withdementia. A patient receiving therapy from system 10 can have reducedintegrity of white matter tracts innervating limbic structures such asthe fornix (e.g. at least the fornix) as determined by fractionalanisotropy maps using diffusion tensor imaging. System 10 can beconstructed and arranged to achieve at least one of: treats memoryimpairment; improves memory function; treats cognitive function loss;reverses synaptic loss; improves cognitive function; reduces degradationof cognitive function; promotes neurogenesis in the hippocampus ofpatient P's brain B; drives neurotrophin expression; regulates one ormore biomarkers related to Alzheimer's Disease such as amyloid-beta,tau, and/or phosphorylated tau; regulates BDNF expression; increasesneurotransmitter release such as acetylcholine; or improves glucoseutilization in the temporal lobe, the parietal lobe or both lobes of thepatient's brain.

In some embodiments, a combination of treatment therapies can bedelivered by system 10 to provide influencing of multiple neuronaltypes. Stimulator 100 can be constructed and arranged to delivermultiple therapies, such as two or more stimulation therapies selectedfrom the group consisting of: electrical stimulation; magneticstimulation; optical stimulation (e.g. visible, ultraviolet and/orinfrared light); sound stimulation (e.g. ultrasound or subsonic waves);chemical stimulation (e.g. a drug or other agent); and combinations ofthese, such as described hereabove. For example, it can be desirable toconcurrently influence, via chemical, electrical and/or otherstimulation, the neurons in the fornix, hippocampus and/or otherportions of brain B to achieve an improved result. Such a system 10utilizing multiple forms of treatment therapy can be similar to thatwhich is disclosed, for example, in U.S. Pat. No. 5,782,798, the contentof which is incorporated herein by reference in its entirety. Inaddition to affecting the deep brain, it can be desirable for system 10to concurrently affect one or more other portions of the brain.

In some embodiments, system 10 is constructed and arranged to provideone or more pharmaceutical or other agents, such as an agent deliveredorally, via an injection, or delivered by a component of system 10. Insome embodiments, system 10 is constructed and arranged to provide acholinesterase inhibitor medication or other agent to patient P.Stimulation element 150 a and/or 150 b can be constructed and arrangedto deliver one or more pharmaceutical or other agents, such as whenstimulation 150 a and/or 150 b are further configured as a drug deliveryelement or other liquid or solid dispensing element.

As described above, controller 200 is constructed and arranged to setone or more treatment stimulation parameters 107 of system 10, such asan initial setting of one or more treatment stimulation parameters 107(e.g. to cause an initial treatment stimulation energy to be deliveredto brain B) or a modification to an existing set of one or moretreatment stimulation parameters 107 (e.g. to modify the treatmentstimulation energy being delivered to brain B). Initial settings oftreatment stimulation parameters 107 and/or modifications to existingsettings can be made to provide sufficient therapy (e.g. cause a desiredevent) and/or to reduce the likelihood or effect of one or more adverseevents. Setting of one or more treatment stimulation parameters 107 canbe made by an operator of system 10 using controller 200, such as anoperator who is a clinician or other caregiver to patient P.Alternatively or additionally, setting of one or more treatmentstimulation parameters 107 can be performed automatically orsemi-automatically by system 10, such as in a closed loop fashion basedon information received from diagnostic tool 300 or another component ofsystem 10.

Controller 200 comprises user interface 201, such as a user interfaceconfigured to provide information to and/or receive commands from anoperator of system 10. User interface 201 can comprise one or more userinput and/or user output components selected from the group consistingof: a touchscreen; a graphical and/or alphanumeric screen; a keypad; amouse; and combinations of these. Controller 200 can comprise one ormore discrete controllers, such as one or more handheld devicesconfigured to program or otherwise communicate with stimulator 100and/or diagnostic tool 300. Pathway 20 can comprise a uni-directional orbi-directional communication pathway between controller 200 andstimulator 100. Pathway 20 can comprise one or more physical conduitssuch as electrically conductive wires and/or optical fibers.Alternatively or additionally, pathway 20 can comprise a wirelesscommunication pathway, such as a transmission of electromagnetic wavessuch as is used in wireless radiofrequency (RF) communications.

Diagnostic tool 300 can comprise a user interface 301, such as a userinterface configured to provide information to and receive commands froman operator of system 10. User interface 301 can comprise one or moreuser input and/or user output components selected from the groupconsisting of: a touchscreen; a graphical and/or alphanumeric screen; akeypad; a mouse; and combinations thereof. As described above,diagnostic tool 300 is constructed and arranged to measure one or morepatient parameters and produce diagnostic data 305 which is determinedbased on the one or more measured patient parameters. Diagnostic data305 can be displayed on user interface 301 (such as heart rateinformation, blood pressure information, or other data corresponding toa measured patient parameter that is displayed on user interface 301).In some embodiments, diagnostic tool 300 can communicate directly withcontroller 200 and/or stimulator 100, such as via a wired or wirelessconnection as described herein, such that diagnostic data 305 isrecorded by controller 200 and/or stimulator 100, such as toautomatically and/or semi-automatically modify one or more stimulationparameters 105.

As described herein, diagnostic data 305 can be used to determine if anadverse event has occurred or is about to occur. Treatment stimulationparameters 107 can be set at a level below or otherwise different thanthe stimulation threshold at which the adverse event occurred, such asat a safety margin below or otherwise away from that stimulationthreshold (e.g. a voltage or current level that is less than the levelcausing the adverse event). In some embodiments, one or more treatmentstimulation parameters 107 are modified based on a stimulation threshold(e.g. modified to a level at or below the stimulation threshold, such asat a safety margin below the stimulation threshold at which an adverseevent occurred). For example, an adverse event that occurs at a signalvoltage of 6 Volts, may result in delivering therapy at 5 Volts (a 16.6%safety margin), at 4 Volts (a 33.3% safety margin) or at 3 Volts (a 50%safety margin).

Diagnostic tool 300 can comprise one or more diagnostic devices, such asone or more devices selected from the group consisting of: heart ratemonitor; EKG measurement device; oximeter; combined heart rate andoximeter device such as a pulse oximeter; blood pressure measurementdevice; neuronal activity measurement device; EEG measurement device;evoked response potential (ERP) measurement device; neurochemicalanalysis device; memory test device; memory test form; respirationmeasurement device; sweat measurement device; skin conductivitymeasurement device; pH measurement device; body motion measurementdevice; imaging device; and combinations of these. Diagnostic tool 300can be constructed and arranged to detect and/or record an adverseevent, such as an adverse event selected from the group consisting of:undesirable heart rate; undesirable respiration rate; undesirablesweating; undesirable hallucinations; undesirable tingling; flushing;undesirable psychiatric effect; undesirable cognitive effect; unpleasantgeneralized warming; undesirable perceptions described as déjà vu;seizure; synchronized neuronal firing pattern; undesired neural responsetime; undesired brain state; undesired theta phase; undesired p300amplitude; and combinations of these.

In some embodiments, diagnostic tool 300 comprises two independentdiagnostic measurement devices, for example two devices whose diagnosticdata are used in combination. For example, diagnostic tool 300 cancomprise a blood pressure measurement device and a heart ratemeasurement device, such as to identify patient discomfort or otherpatient issue (e.g. a falsehood or other inaccurate statement made bythe patient that can be detected through analysis of a patient parametersuch as heart rate and/or blood pressure).

Diagnostic tool 300 can comprise a memory test such as a verbal, visual,motor function and/or spatial memory test. Diagnostic tool 300 can beconstructed and arranged to detect and/or record a memory recall event,such as a tool including an EEG measurement device and/or a form (e.g. apaper form or electronic form) configured to manually record the resultsof a memory test.

In embodiments where diagnostic tool 300 comprises an EKG measurementdevice, one or more treatment stimulation parameters 107 can be setbased on a stimulation threshold at which undesired EKG activity (e.g.tachycardia or an arrhythmia) is identified in diagnostic data 305.

In embodiments where diagnostic tool 300 comprises a neuronal activitymeasurement device, diagnostic tool 300 can be constructed and arrangedto measure a neuronal parameter selected from the group consisting of:single neuron activity; local field potential (LFP); event relatedpotential (ERP); electroencephalogram reading; electrocorticogramreading; and combinations of these. In these embodiments, a stimulationthreshold (e.g. a stimulation threshold at which an adverse event isrecorded by diagnostic tool 300) can be determined when an adverse eventoccurs that is selected from the group consisting of: seizure;synchronized neuronal firing pattern; undesired neural response time;undesired brain state; undesired theta phase; undesired p300 amplitude;and combinations of these.

In embodiments where diagnostic tool 300 comprises an event relatedpotential (ERP) measurement device, one or more treatment stimulationparameters 107 can be set based on a stimulation threshold at whichundesired ERP activity is identified in diagnostic data 305.

In embodiments where diagnostic tool 300 comprises a blood pressuremeasurement device, one or more treatment stimulation parameters 107 canbe set based on a stimulation threshold at which undesired bloodpressure readings (e.g. above a threshold) are identified in diagnosticdata 305. In these embodiments, diagnostic tool 300 can further comprisea heart rate measurement device, such that diagnostic data comprisesboth blood pressure readings and heart rate readings, such as when astimulation threshold is based on the occurrence of high blood pressureand/or tachycardia.

In embodiments where diagnostic tool 300 comprises a blood oxygenmeasurement device, one or more treatment stimulation parameters 107 canbe set based on a stimulation threshold at which undesired blood oxygenreadings are identified in diagnostic data 305.

In embodiments where diagnostic tool 300 comprises a body motionmeasurement device, one or more treatment stimulation parameters 107 canbe set based on a stimulation threshold at which undesired body motion(e.g. a tremor) is identified in diagnostic data 305.

In embodiments where diagnostic tool 300 comprises a neurochemicalanalysis device, the neurochemical analysis device can be constructedand arranged to measure a parameter selected from the group consistingof: neurotransmitter level (GABA, glutamate, acetylcholine, dopamine,epinephrine, etc.); a pH concentration; an ion concentration; a lactatelevel; cerebral blood flow; glucose utilization; oxygen extraction; andcombinations of these. One or more treatment stimulation parameters 107can be set based on a stimulation threshold at which undesiredneurochemical activity and/or level is identified in diagnostic data305.

In embodiments where diagnostic tool 300 comprises an imaging device,one or more treatment stimulation parameters 107 can be set based on astimulation threshold at which an undesired patient condition isidentified in one or more images (diagnostic data 305) produced by theimaging device. Diagnostic tool 300 can comprise an imaging deviceselected from the group consisting of: standardized Low Resolution BrainElectromagnetic Tomography (sLORETA) device; functional magneticresonance imaging (fMRI); MagnetoEncephalography (MEG); and combinationsof these, such as when used to produce diagnostic data 305 thatquantifies or qualifies the effects of receiving stimulation from system10. In these embodiments, one or more images produced by diagnostic tool300 can be used to optimize therapy or reduce an adverse event, such aswhen used to select an electrode to receive stimulation energy based onits position relative to a target as described herein. One or moreimages produced by diagnostic tool 300 can be use to select one or morestimulating elements from a set of multiple stimulating elements (e.g.to select one or more electrodes from a set of multiple electrodes basedon an image of the multiple electrodes in reference to a targetstimulation location such as the fornix).

In some embodiments, diagnostic tool 300 produces data (e.g. image data)to assess axonal pathways, such as an assessment performed duringstimulation of the axonal pathways or locations proximate the assessedpathways. In these embodiments, diagnostic data 305 produced bydiagnostic tool 300 can be used to identify one or more axonal pathwaysthat may be necessary or at least desirable to optimize therapeuticbenefit from the stimulation provided by system 10. Diagnostic tool 300can comprise at least a diffusion tension imaging (DTI) device and/or atractography-activation model (TAM) used to identify the pathwaysstimulated by system 10. The TAM can consist of: anatomical anddiffusion-weighted imaging data acquired on the patient; probabilistictractography from the brain region surrounding the stimulation element150 a and/or 150 b; finite element models of the electric fieldgenerated by stimulator 100; and/or application of the electric fieldproduced by stimulation element 150 a and/or 150 b to multi-compartmentcable models of axons, with trajectories defined by the tractography, topredict action potential generation in the pathways. Diagnostic tool 300can be configured to produce clinical data, diffusion tensortractography, and/or computer models of tissue-specific stimulationareas, such as to determine one or more axonal pathways being stimulatedand/or to predict or differentiate the therapeutic benefit of theirstimulation.

Diagnostic tool 300 can comprise a patient assessment recording tool,such as a tool selected from the group consisting of: a form; a paperform; an electronic form; a tablet; a personal computer; a database; andcombinations of these. In these embodiments, the patient assessment cancomprise an assessment selected from the group consisting of: anassessment received verbally from the patient; an assessment received inwritten form from the patient; an assessment made by a caregiver of thepatient; and combinations of these. The patient assessment can comprisean assessment of a patient state selected from the group consisting of:depression; paranoia; schizophrenia; suicidality; suicide ideation;apathy; anxiety; mania; and combinations of these. Diagnostic tool 300can comprise an algorithm configured to analyze data on a patientassessment form or other patient assessment tool.

In some embodiments, diagnostic tool 300 comprises one or more sensors330 as shown. One or more sensors of system 10, such as sensor 330,sensor 230 and/or sensor 430 can comprise a sensing element selectedfrom the group consisting of: neuronal activity sensor; EEG sensor;local field potential (LFP) sensor; neurochemical sensor; pH sensor;pressure sensor; blood pressure sensor; optical sensor; blood gassensor; blood oxygen sensor; magnetic sensor; strain gauge; andcombinations of these. Sensor 330, sensor 230 and/or sensor 430 cancomprise an implanted or external sensor. Stimulating element 150 aand/or 150 b can comprise sensor 330. Sensor 330, sensor 230 and/orsensor 430 can comprise at least one electrode. System 10 can beconstructed and arranged to provide closed loop stimulation based on oneor more signals received from one or more of sensors 330, 230 and/or430.

As described hereabove, one or more portions of stimulator 100 can beimplanted in the patient, such an implantation of stimulation element150 b. Diagnostic tool 300 can be constructed and arranged to gatherdiagnostic data 305 before and/or after implantation of stimulationelement 150 b. In some embodiments, diagnostic tool 300 gathersdiagnostic data 305 to determine a stimulation threshold at least 5minutes after implantation of stimulation element 150 b. In someembodiments, diagnostic tool 300 gathers diagnostic data 305 todetermine a stimulation threshold at least 24 hours after implantationof stimulation element 150 b, or at least 2 weeks after implantation ofstimulation element 150 b.

As described above, controller 200 and stimulator 100 can be constructedand arranged to stimulate brain B with one or more temporary stimulationparameters, test stimulation parameters 106. Diagnostic tool 300 can beconstructed and arranged to measure one or more patient parameters whilebrain B is being stimulated with test stimulation parameters 106,producing diagnostic data 305 correlating to the test stimulationparameters 106. In some embodiments, multiple sets of similar ordissimilar test stimulation parameters 106 are delivered to brain B,while diagnostic tool 300 measures at least one patient parameter andproduces diagnostic data 305. In some embodiments, a series of variedtest stimulation parameters 106 can be delivered to brain B (e.g. astepped or continuous increase in stimulation energy level, such as astepped or continuous increase of a stimulating voltage and/or current),while diagnostic tool 300 measures one or more patient parameters andproduces a set of diagnostic data 305 which is correlated to theparticular level of test stimulation parameters 106 associated with eachsubset of diagnostic data 305. Subsequently, stimulator 100 deliverstreatment stimulation energy comprising one or more treatmentstimulation parameters 107 that are determined from or otherwise basedon the produced diagnostic data 305. In some embodiments, one or moretreatment stimulation parameters 107 are manually programmed intostimulator 100 via controller 200. In some embodiments, system 10 isconstructed and arranged to automatically set one or more treatmentstimulation parameters 107 based on the produced diagnostic data 305.

In some embodiments, diagnostic data 305 produced by diagnostic tool 300is used to determine an initial (e.g. first time) set of treatmentstimulation parameters 107. In some embodiments, diagnostic data 305produced by diagnostic tool 300 is used to modify a pre-existing set oftreatment stimulation parameters 107. In some embodiments, diagnosticdata 305 produced by diagnostic tool 300 is used to determine teststimulation parameters 106, such as diagnostic data 305 collected in aprevious test. In these embodiments, a test stimulation parameter 106can be set based on a stimulation threshold at which an adverse eventwas detected by diagnostic tool 300.

In some embodiments, stimulator 100 stimulates brain B with a first setof test stimulation parameters 106′ for a first time period and a secondset of test stimulation parameters 106″ for a second time period. Thefirst time period and the second time period can comprise relatively thesame length of time or different lengths of time. The first and/orsecond time periods can comprise a time period less than or equal to 24hours, such as less than or equal to 6 hours, 3 hours, 1 hour, 30minutes, 15 minutes, 10 minutes, 5 minutes or 2 minutes. Diagnostic tool300 measures one or more patient parameters during all or a portion ofboth the first time period and the second time period, and producesfirst diagnostic data 305′ and second diagnostic data 305″, representingthe measured at least one patient parameter recorded during the firsttime period and the second time period, respectively. Subsequently,stimulator 100 provides stimulation energy to brain B comprising one ormore treatment stimulation parameters 107 that are determined using orotherwise based on the first diagnostic data 305′ and second diagnosticdata 305″. In these embodiments, treatment stimulation parameters 107can be based on one or more test stimulation parameters 106 associatedwith a desired treatment and/or they can be based on one or more teststimulation parameters 106 associated with avoiding an adverse event,such as described herein.

In some embodiments, the treatment stimulation parameters 107 equal orat least approximate the first set of test stimulation parameters 106′or the second set of test stimulation parameters 106″. The treatmentstimulation parameters 107 chosen can approximate a test stimulationparameter 106 associated with an improved or otherwise desired treatmentof a neurological disease and/or disorder. The improved treatment cancorrespond with a therapeutic benefit such as a desired memory recallwith the patient. Alternatively or additionally, the treatmentstimulation parameters 107 chosen can approximate a test stimulationparameter 106 associated with avoidance of an adverse event. In someembodiments, the treatment stimulation parameters 107 chosen can beproportional or otherwise based on a test stimulation parameter 106associated with avoidance of an adverse event as described hereabove,such as when treatment stimulation parameters 107 are a safety marginbelow the test stimulation parameters 106 at which the adverse eventoccurred, as described herein.

In some embodiments, one or more treatment stimulation parameters 107are manually programmed into stimulator 100 via controller 200.Alternatively, system 10 is constructed and arranged to automaticallyset one or more treatment stimulation parameters 107 based on theproduced diagnostic data 305.

Diagnostic tool 300 used in the first time period and the second timeperiod can comprise one or more diagnostic devices or other tools, suchas are described herein, each producing diagnostic data 305. In someembodiments, diagnostic data 305 produced by a diagnostic tool 300 isused to determine first test stimulation parameters 106′ and/or secondtest stimulation parameters 106″, such as diagnostic data 305 collectedin a previous test performed using diagnostic tool 300. In someembodiments, diagnostic tool 300 comprises a memory test tool, such as aform used to record memory data. In these embodiments, treatmentstimulation parameters 107 can approximate or otherwise be based on thetest stimulation parameters 106 that resulted in a higher memory testscore recorded in one of a set of time periods (e.g. two or more timeperiods) between which one or more test stimulation parameters werevaried.

One or more treatment stimulation parameters 107 can comprise anelectrical stimulation parameter selected from the group consisting of:voltage level such as an average voltage level, rms voltage level and/ora peak voltage level; current level such as an average current level,rms current level and/or a peak current level; power level such as anaverage power level, rms power level and/or a peak power level;frequency of stimulation signal; series of frequencies of thestimulation signal; phase of stimulation signal; pulse width modulationratio; signal pulse width; current density such as current densityapplied to tissue; single electrode selected to receive stimulationenergy; set of electrodes selected to receive monopolar and/or bipolarstimulation energy; and combinations of these. In some embodiments,stimulation element 150 b comprises a lead inserted into brain B andcomprising multiple electrodes, and a treatment stimulation parameter107 or other stimulation parameter 105 can represent a selection (e.g. asubset) of one or more specific electrodes of the lead to receivestimulation energy. The selection of electrodes can comprise a singleelectrode, a pair of electrodes, or more than two electrodes, such asone or more electrodes that receive monopolar or bipolar energy. In someembodiments, a stimulation parameter 105 comprises a signal voltage ofbetween 0.1 Volts and 10.0 Volts, such as a voltage between 1.0 Voltsand 6.0 Volts, or between 1.0 Volts and 3.0 Volts. In some embodiments,a stimulation parameter 105 comprises a voltage less than or equal to9.0 Volts, such as less than or equal to 8.0 Volts, 7.0 Volts, 6.0Volts, 5.0 Volts, 4.0 Volts or 3.5 Volts. In some embodiments, astimulation parameter 105 comprises a signal frequency between 2 Hz and1000 Hz, such as a frequency of approximately 130 Hz. Energy deliverycan be given in a series of on and off times, such as when a stimulationparameter 105 comprises an on-time of approximately 30 μseconds to 200μseconds, such as with an on time of 90 μseconds. A stimulationparameter 105 can comprise a parameter associated with duration ofenergy delivery, such as a parameter corresponding to continuousdelivery of energy (e.g. continuous delivery of pulsed energy) or aparameter corresponding to intermittent energy delivery comprising oneor more energy delivery periods ranging from thirty minutes to 24 hours.

In some embodiments, a stimulation parameter 105 comprises a lightstimulation parameter selected from the group consisting of: power oflight delivered to tissue; frequency of light delivered to tissue;modulation parameter of light delivered to tissue; and combinations ofthese.

In some embodiments, a stimulation parameter 105 comprises a soundstimulation parameter selected from the group consisting of: amplitudeof sound delivered to tissue; frequency of sound delivered to tissue;modulation parameter of sound delivered to tissue; and combinations ofthese.

In some embodiments, a stimulation parameter 105 comprises an agentdelivery stimulation parameter selected from the group consisting of:mass of agent delivered to tissue; volume of agent delivered to tissue;concentration of agent delivered to tissue; delivery rate of agentdelivered to tissue; and combinations of these.

In some embodiments, controller 200 and/or another component of system10 are constructed and arranged to set at least one treatmentstimulation parameter 107 based on a stimulation threshold at which anadverse event is detected by diagnostic tool 300, such as an adverseevent as described hereabove. In these embodiments, the at least onetreatment stimulation parameter 107 can be set to a level at or belowthe stimulation threshold, such as at a safety margin below thestimulation threshold as described hereabove.

In some embodiments, controller 200 and/or another component of system10 are constructed and arranged to set at least one treatmentstimulation parameter 107 based on a stimulation threshold at which adesired event is detected by diagnostic tool 300. Patient desired eventsinclude events selected from the group consisting of: recall of adesired memory; achievement of desired memory learning; desired level ofneuronal activity; acceptable physiologic condition such as anacceptable heart rate or acceptable level of neuronal activity;experiential phenomena such as those described in epilepsy literature;and combinations of these. In these embodiments, the at least onetreatment stimulation parameter 107 can be set to a level at or abovethe stimulation threshold, such as at a pre-determined percentage abovethe stimulation threshold. In these embodiments, the at least onetreatment stimulation parameter 107 can also be set based on a secondstimulation threshold at which an adverse event occurred, such as asafety margin below the adverse event stimulation threshold. Forexample, a memory recall event may be recorded by diagnostic tool 300 ata stimulation voltage of X Volts, and an adverse event may be recordedby diagnostic tool 300 at a stimulation voltage of Y Volts, where Y isgreater than X. A treatment stimulation parameter 107 can be set to asignal voltage between X Volts and Y Volts.

System 10 can be constructed and arranged to provide open loopstimulation to brain B. Alternatively or additionally, system 10 can beconstructed and arranged to provide closed loop stimulation to brain B,such as closed loop stimulation based on diagnostic data 305 provided bydiagnostic tool 300 and/or a signal provided by one or more of sensors330, 430 and 230, or a separate implanted or external sensor, such assensor 430 described in reference to FIG. 4 herebelow.

In some embodiments, diagnostic tool 300 and/or another component ofsystem 10 comprises data logging assembly 350. Data logging assembly 350can be constructed and arranged to record one or more events that occurduring delivery of test stimulation energy using test stimulationparameters 106, such as when stimulation energy is varied. Data loggingassembly 350 can be configured to record diagnostic data 305, such as todetermine a minimum, maximum, average and/or other statistical value ofdiagnostic data 305 (e.g. a maximum heart rate and/or a maximum bloodpressure that occurs during delivery of test stimulation energy). Insome embodiments, data logging assembly 350 comprises an assembly with abutton that a patient can activate (e.g. press), such as during apatient adverse event or a memory recall event, as noticed by thepatient. In some embodiments, at least a portion of data loggingassembly 350 can be at a location remote from the patient, such as atone or more file locations accessible via the Internet or otherinformation access network. Diagnostic data 305 from multiple patientscould be stored in one or more locations remote from those patients.Diagnostic data 305 recorded by one or more diagnostic tools 300 duringdiagnostic tests performed on one or more patients can be processed,analyzed and/or otherwise used to determine one or more treatmentstimulation parameters 107 for one or more patients.

Referring now to FIG. 2 a flow chart of a series of steps for treating apatient with a stimulation system is illustrated, consistent with thepresent inventive concepts. The method comprises STEPs 510 through 550,which can be performed using one or more components of system 10 of FIG.1 described hereabove. In STEP 510, a patient is selected forimplantation. In a preferred method, the patient is screened forcandidacy as described in reference applicants co-pending U.S. patentapplication Ser. No. 13/655,652, entitled “Deep Brain Stimulation ofMemory Circuits in Alzheimer's Disease”, filed Oct. 19, 2012, thecontent of which is incorporated herein by reference in its entirety. Insome embodiments, the selected patient is a patient diagnosed and/orprognosed with a cognitive disorder selected from the group consistingof: Alzheimer's Disease (AD) such as Mild or Moderate Alzheimer'sDisease; probable Alzheimer's Disease; a genetic form of Alzheimer'sDisease; Mild Cognitive Impairment (MCI); hippocampal damage such ashippocampal damage due to Alzheimer's disease, anoxia, epilepsy ordepression; neuronal loss; neuronal damage; chemotherapy induced memoryimpairment; epilepsy; a seizure disorder; dementia; amnesia; a memorydisorder such a spatial memory disorder; cognitive impairment associatedwith Schizophrenia; Parkinson's Disease related cognitive impairment ordementia; and combinations of these. Additionally or alternatively, thepatient can be selected to treat negative symptoms of a disease ordisorder selected from the group consisting of: schizophrenia;depression; other conditions of reversible impaired memory or cognition;and combinations of these.

In STEP 520, at least one imaging procedure is performed on the patient,collecting at least one patient image. In some embodiments, the imagingprocedure is an MRI procedure performed to identify the fornix of thepatient and/or one or more other brain locations. Alternatively oradditionally, different patient imaging procedures can be used includingimaging procedures selected from the group consisting of X-ray;ultrasound imaging; fMRI; PET scan; and combinations of these. Multipleimaging procedures can be performed, such as similar imaging proceduresperformed at different times, or different imaging procedures performedat the same or different times. In one embodiment, a first imagingprocedure is performed at least 7 days prior to a second imagingprocedure. In another preferred embodiment, a first imaging procedure isan MRI procedure and a second imaging procedure is selected from thegroup consisting of: a second MRI procedure; an X-ray; an ultrasoundimaging procedure; an fMRI; a PET scan; and combinations of these.Multiple patient images, collected in one or more similar or dissimilarimaging procedures, can be collected. These images can be used incombination, in comparison, or both. In some embodiments, the twoprocedures are performed at different times and one or more patientparameters are compared, such as parameters selected from the groupconsisting of: brain size; brain shape; and brain thickness. In someembodiments, an amyloid PET scan can be used to assess the presence ofamyloid in a patient. In some embodiments, a resting state BOLD fMRIsequence is performed to evaluate Default Mode Network or other brainstate. In some embodiments, Diffusion Tensor Imaging and tractographyare performed, such as to create an image of microstructures of thebrain to assess white matter abnormalities (e.g. of the fornix).

In STEP 530, at least a portion of a brain stimulator can be implanted,such as an implantation of one or more portions of brain stimulator 100described in reference to FIG. 1 hereabove and/or stimulator 100described in reference to FIG. 4 herebelow. The one or more implantableportions of brain stimulator 100 can be implanted in one or moresurgeries. The surgery can include implantation of a lead comprising oneor more electrodes, such as one or more electrodes to be positionedproximate the fornix of the patient's brain B. One or more stimulatingelements such as electrodes can be implanted in a location selected fromthe group consisting of: in the Papez Circuit of the patient's brain;approximately 2 mm anterior and parallel to the vertical portion of thefornix; in the optic tract such that the ventral-most contact is 2 mmabove the dorsal surface of the optic tract; approximately 5 mm from themidline; and combinations of these. A post-operative imaging proceduresuch as an MRI can be performed to assess and/or confirm position of oneor more implanted electrodes or other components of the system, such asto confirm location of multiple electrodes relative to the fornix orother target location within the patient's brain. The diagnostic toolcan be an imaging device, and the diagnostic data can include one ormore images produced by the diagnostic device used to select one or moreelectrodes or other stimulating elements configured to receivestimulation energy. The one or more stimulating elements can be selectedbased on their proximity and/or relative position to a stimulationtarget, such as the fornix. For example a first electrode providingstimulating energy generating a first set of diagnostic data can beselected over a second electrode providing stimulating energy andgenerating a second set of similar diagnostic data (e g similartherapeutic benefit) based on information provided by an imaging device(e.g. when the first electrode is in a more desirable position relativeto a stimulation target than the second electrode). In some embodiments,electrode selection is made based on image data to prevent stimulationon non-target tissue (i.e. tissue whose stimulation is to be avoided orat least reduced).

In alternative embodiments, brain stimulation is provided by anexternal, non-invasive stimulation device (i.e. one or more fullynon-implanted stimulation system components). In embodiments includingan implanted stimulator or a stimulator including at least an implantedportion, at least one stimulation element can be implanted in, on ornear the brain of a patient. The at least one stimulation element of thestimulator can be positioned in, on or near the brain of the patientbased on the at least one patient image. The at least one stimulationelement can be placed via a visual analysis of the at least one image,and/or one or more mathematical or other computational analysis oranalyses of the patient image. In some embodiments, the at least onestimulation element is positioned in and/or proximate the fornix of thepatient's brain, as has been described in hereabove. In anotherembodiment, the at least one stimulation element, such as a stimulationelement comprising at least two electrodes, is positioned to providebipolar stimulation of the fornix or other brain tissue. The at leastone stimulation element can comprise at least one electrode configuredto deliver electrical energy. Proper positioning of the stimulationelement can be confirmed after placement, such as with a subsequent MRIor other patient image.

The stimulation element, such as one or more stimulation elements 150 ofstimulator 100 of FIG. 1, can comprise an electrical stimulation elementsuch as an electrode or a magnet such as an electromagnet. Alternativelyor additionally, the stimulation element can comprise an opticalstimulation element, such as a visible light element; an infrared lightelement; and combinations of these. Alternatively or additionally, thestimulation element can comprise a chemical stimulation element, such asa drug or other agent delivery assembly. The drug delivery assembly canbe configured to deliver one or more of: biologically active molecules;neurotransmitters; and neurotrophic factors. The stimulation element candeliver one or more drugs or pharmaceutical agents, and delivery rate ordrug concentration can be determined based on patient tolerance, such asa tolerance determined in a titration procedure performed usingdiagnostic tool 300 of FIG. 1. In a particular embodiment, thestimulation element is constructed and arranged to deliver acholinesterase inhibitor. In another particular embodiment, an electrodeand a second stimulation element is included. The second stimulationelement can comprise an element selected from the group consisting of: asecond electrode; a magnet; an optical element; a chemical or otheragent delivery assembly; and combinations of these.

In STEP 540, one more diagnostic tests can be performed, such as usingdiagnostic tool 300 of FIG. 1 to gather diagnostic data 305, asdescribed hereabove. The diagnostic data collected can be collectedduring stimulation with one or more test stimulation parameters, such astest stimulation parameters 106 described hereabove. Diagnostic tool 300can be used to reposition one or more stimulation elements, such as arepositioning performed during the implantation procedure or during asubsequent surgical or minimally invasive procedure. This repositioningcan be based on maximizing a desirable patient effect, such asmaximizing recalled memory or memories. Alternatively or additionally,the repositioning can be based on minimizing an adverse event, such asto minimize chest pain; undesired EKG signal or signals; undesired EEGsignal or signals; labored breathing; twitching; undesired heart rate;undesired blood pressure; and combinations of these. Alternatively oradditionally, the repositioning can be based on minimizing aneurological condition of the patient, such as a level of one or moreof: paranoia; psychosis; anxiety; depression; and confusion.

Diagnostic data 305 can be gathered prior to, during or afterimplantation of one or more portions of the stimulation system, such asdiagnostic data gathered at least two weeks after implantation of astimulator portion. During or after implantation of the implantedstimulator portion, a decision can be made to adjust at least onestimulation parameter based on the diagnostic data 305. The adjustedparameter can be a stimulation parameter selected from the groupconsisting of: voltage level such as an average voltage level, rmsvoltage level and/or a peak voltage level; current level such as anaverage current level, rms current level and/or a peak current level;power level such as an average power level, rms power level and/or apeak power level; frequency of stimulation signal; series of frequenciesof the stimulation signal; phase of stimulation signal; pulse widthmodulation ratio; signal pulse width; current density such as currentdensity applied to tissue; single electrode selected to receivestimulation energy; set of electrodes selected to receive monopolarand/or bipolar stimulation energy; agent delivery rate; physiologicconcentration; power of light delivered to tissue; frequency of lightdelivered to tissue; a modulation parameter of light delivered totissue; amplitude of sound delivered to tissue; frequency of sounddelivered to tissue; a modulation parameter of sound delivered totissue; mass of agent delivered to tissue; volume of agent delivered totissue; concentration of agent delivered to tissue; delivery rate ofagent delivered to tissue; and combinations of these. Diagnostic data305 can be used to set initial stimulation parameters and/or to modifyexisting stimulation parameters.

The implantation procedure can include a calibration or titrationprocedure, such as procedures which use a diagnostic tool of the presentinventive concepts to optimize or otherwise modify one or morestimulation parameters (e.g. one or more test stimulation parameters ortreatment stimulation parameters) such as one or more stimulationparameters selected from the group consisting of: an electromagneticenergy delivery parameter such as voltage or current delivered; amagnetic energy delivery parameter such as field strength or fieldorientation; a light delivery parameter such as wavelength or magnitudeof light delivered; a sound delivery parameter such as frequency oramplitude of a delivered sound wave; a chemical delivery parameter suchas a concentration of a drug or other agent delivered or a rate of anagent delivered; and combinations of these. If successful calibration ortitration cannot be achieved, the implanted stimulator portion can beremoved and the procedure abandoned. Alternatively, if a particularadverse event occurs, the implanted stimulator portion can be explanted.Typical adverse events causing explantation can include but are notlimited to: chest pain; labored breathing; twitching; unacceptable EKGsignal or combination of signals; unacceptable EEG signal or combinationof signals; undesired heart rate; undesired blood pressure; andcombinations of these. Alternatively or additionally, typical adverseevents causing explantation can be an unacceptable neurological statesuch as an unacceptable level of one or more of: paranoia; psychosis;anxiety; depression; and confusion.

STEP 540 can include multiple diagnostic tests performed by one or morediagnostic tools of the present inventive concepts, such as the one ormore diagnostic tools 300 described in reference to FIG. 1 hereabove.The diagnostic procedure can include a series of diagnostic testsperformed relatively continuously. The diagnostic procedure can includeconfirming electrode placement via an impedance measurement, for exampleduring and/or after an implantation step. The diagnostic procedure caninclude measuring toxicity at one or more patient locations, and astimulation parameter can be adjusted if a measured toxicity exceeds athreshold. The diagnostic procedure can include a patient memory testthat produces results, and a stimulation parameter can be adjusted ifthe results exceed a threshold. The diagnostic procedure can include alearning task such as a task selected from the group consisting of: amemory task; a cognitive task; a motor task; a standardized test such asa full or partial ADAS-Cog or California Verbal Learning test; andcombinations of these. Based on the outcome from any of the abovedescribed diagnostic procedures, at least one stimulation parameter canbe adjusted (e.g. a test stimulation parameter and/or a treatmentstimulation parameter), for example an adjustment of a parameterselected from the group consisting of: voltage level; current level;current density level; a duty cycle parameter such as a pulse widthduration; an energy delivery frequency; and combinations of these.

STEP 540 can include sensing a characteristic indicative of the extentof the cognitive disorder and generating a sensor signal and regulatingthe operation of the stimulator in response to the sensor signal. Insome embodiments, sensing a characteristic indicative of the extent ofthe cognitive disorder and generating a sensor signal can comprisedetecting a neurochemical characteristic of the cognitive disorder, forexample the signal may represent a neurochemical characteristic selectedfrom the group consisting of: neurotransmitter level, pH concentration,ion concentration, lactate level, cerebral blood flow, glucoseutilization, and oxygen extraction. In some embodiments, sensing acharacteristic indicative of the extent of the cognitive disorder andgenerating a sensor signal can comprise detecting anelectrophysiological characteristic of the cognitive disorder, forexample an electrophysiological characteristic is selected from thegroup consisting of: the activity of one or more neurons, collectivelyor singly; local field potentials; event related potentials (ERPs); acharacteristic collected by an electroencephalogram; a characteristiccollected with MagnetoEncephalography (MEG); a characteristic collectedby an electrocorticogram; and combinations of these.

STEP 540 can include sensing a characteristic indicative of the extentof the cognitive disorder, generating a sensor signal, and, if thesensor signal is outside of a predetermined threshold, treating thecognitive disorder by initiating stimulation therapy by the stimulator.STEP 540 can include determining the threshold of one or morestimulation parameters (i.e. the “stimulation threshold” as describedherein) associated with an adverse event, such as an adverse event thatoccurs during continuous or intermittent adjustment of one or morestimulation parameters as described in reference to FIG. 3 herebelow.STEP 540 can include determining the stimulation threshold of one ormore stimulation parameters associated with onset of a therapeuticbenefit to the patient, such as a recalled memory event or an improvedmemory test score.

In some embodiments, multiple portions of brain tissue are stimulatedsequentially, such as by sequentially stimulating a set of multipleelectrodes. For example, a lead comprising a set of multiple electrodescan be sequentially stimulated in order to identify one or moreelectrodes that avoid an adverse event and/or provide enhancedtherapeutic benefit to the patient. In these embodiments, two or moreelectrodes can be stimulated with bipolar stimulation energy.

STEP 550 comprises setting one or more treatment stimulation parameters(e.g. treatment stimulation parameters 107 of FIG. 1 describedhereabove) based on diagnostic data 305 collected during STEP 540 orother diagnostic data collected by a diagnostic tool of the presentinventive concepts. In some embodiments, the treatment stimulationparameters approximate one or more test stimulation parameters at whicha desirable result was achieved, such as a desired therapeutic benefit.In some embodiments, the treatment stimulation parameters are a safetymargin below a level at which a test stimulation parameter resulted inan adverse event, as has been described in detail in reference to FIG. 1hereabove.

One or more portions of STEP 540 can be performed prior to STEP 520,prior to STEP 530 and/or after STEP 550. STEP 540 can be performedmultiple times, such as one or more times prior to STEP 520, one or moretimes after STEP 520 and before STEP 530, one or more times after STEP530 and before STEP 550, and/or one or more times after STEP 550. Insome embodiments, STEPs 520 and 550 are performed multiple times. Insome embodiments, multiple performances of STEP 540 are performed (e.g.multiple productions of diagnostic data 305 at multiple test stimulationparameters 106), and the collective diagnostic data 305 is used toproduce a set of treatment stimulation parameters 107 set in asubsequent step 550. In some embodiments, multiple performances of STEP540 are performed and each result in a STEP 550 being performed in whichone or more treatment stimulation parameters 107 are initiated and/ormodified.

Referring now to FIG. 3, a flow chart of a series of steps forperforming STEP 540 of FIG. 2 is illustrated, consistent with thepresent inventive concepts. STEPs 541 through 546 of FIG. 3 can beperformed using one or more components of system 10 of FIG. 1 asdescribed hereabove. In STEP 541, a set of test stimulation parameters106 are programmed into a stimulation device (e.g. a first set of teststimulation parameters 106′ programmed into stimulator 100 usingcontroller 200 as described in reference to FIG. 1). In STEP 542, one ormore portions of brain tissue of a patient (e.g. tissue of brain B ofFIG. 1) are stimulated using the test stimulation parameters 106. InSTEP 543, diagnostic data 305 is gathered with one or more diagnostictools (e.g. diagnostic data 305 gathered by diagnostic tool 300 ofFIG. 1) during stimulation with the test stimulation parameters 106. InSTEP 544, a determination of testing completeness is performed. Iftesting is not complete, STEP 547 is performed in which one or more ofthe test stimulation parameters 106 are adjusted (e.g. a second set oftest stimulation parameters 106″ programmed into stimulator 100 usingcontroller 200). Subsequently, STEP 542 is performed again, stimulatingbrain B tissue with the adjusted test stimulation parameters 106. STEP543 is also performed again, gathering new diagnostic data 305 at theadjusted test stimulation parameters 106. STEP 544 is performed again,determining test completeness. If test is not complete, STEPs 547, 542,543 and 544 are continuously repeated until testing is complete.

In some embodiments, repeated stimulation with initial and adjusted teststimulation parameters 106 includes incremental increases or decreasesof a test stimulation parameter 106 such a series of increases instimulation voltage and/or current as described hereabove. In someembodiments, a first test stimulation parameter 106 comprises a voltagelevel below 3.0 Volts, and a second and subsequent test stimulationparameters 106 comprise values correlating to sequentially increasingthe voltage (e.g. in 0.1, 0.2, 0.3, 0.4 or 0.5 Volt increments) until anadverse event and/or a therapeutic benefit is recorded by a diagnosticdevice of the present inventive concepts. In some embodiments, the teststimulation parameter 106 used does not exceed a maximum, such as amaximum less than or equal to approximately 10.0 Volts, 9.0 Volts, 8.0Volts or 7.0 volts. In some embodiments, the voltage or other teststimulation parameter 106 level is increased slowly, such as anincrement made in time intervals of approximately at least 0.5 seconds,2.0 seconds, 5.0 seconds, 10.0 seconds or 30.0 seconds.

In some embodiments, a set of test stimulation parameters 106 used inmultiple steps 542 include at least one test stimulation parameter 106in which no stimulation is performed (e.g. a test stimulation parameter106 of 0.0 Volts). In these embodiments, a therapeutic benefit ofstimulation can be confirmed (e.g. by the absence of the benefit when nostimulation was given, such as when the diagnostic device comprises amemory test tool as described herein wherein a higher score is achievedwith one set of test stimulation parameters 106).

After testing completeness has been confirmed in STEP 544, STEP 545 isperformed in which an assessment of the diagnostic data 305 produced bythe one or more diagnostic tools 300 is assessed to determine anoptimized set of one or more treatment stimulation parameters to be usedto stimulate the brain tissue of the patient.

In STEP 550, the optimized set of treatment stimulation parameters 107are programmed into the stimulation device, such as is described inreference to STEP 550 of FIG. 2 hereabove. In some embodiments, thetreatment stimulation parameters 107 are a safety margin below a levelat which a test stimulation parameter 106 resulted in an adverse event,as has been described in detail in reference to FIG. 1 hereabove.

In some embodiments, a first series of STEPs 542 through 547 areperformed with a first set of test stimulation parameters 106 during afirst time period to gather a first set of diagnostic data 305 with adiagnostic tool 300 of the present inventive concepts, and a secondseries of STEPs 542 through 547 are performed with a second set of teststimulation parameters 106 during a second time period to gather asecond set of diagnostic data 305. The treatment stimulation parameters107 can be based on the first set of test stimulation parameters 106and/or the second set of test stimulation parameters 106, such as whenthe chosen set of treatment stimulation parameters 107 avoids an adverseevent and/or causes a therapeutic benefit to the patient or otherdesired event. Accordingly, a third and additional set of teststimulation parameters 106 can be delivered in a third and additionaltime periods. The various time periods can be similar or dissimilar inlength of time. In some embodiments, one or more time periods comprise alength of time less than 24 hours, such as less than 6 hours, less than3 hours, less than 1 hour, less than 30 minutes, less than 15 minutes,less than 10 minutes, less than 5 minutes or less than 2 minutes. Any orall of the test stimulation parameters 106 can be based on diagnosticdata 305 gathered by a diagnostic tool 300 of the present inventiveconcepts during a previous test or treatment stimulation.

Referring now to FIG. 4, a schematic view of an electrical stimulationdevice is illustrated, consistent with the present inventive concepts.Stimulation device 100 delivers electrical stimulation energy includinga stimulus pulse frequency that is controlled by programming a value toa frequency generator 412 (e.g. a programmable frequency generator)using bus 402. The frequency generator 412 provides an interrupt signalto microprocessor 410 through an interrupt line 401 when each stimuluspulse is to be generated. The programmable frequency generator 412communicates with a pulse width control module 414 via pathway 404. Thefrequency generator 412 can be implemented by a commercial device modelCDP1878 sold by Harris Corporation. The amplitude for each stimuluspulse is programmed to a digital to analog converter 416 using bus 402.The analog output is conveyed through a conductor 403 to an outputdriver circuit 418 to control stimulus amplitude.

Microprocessor 410 also programs pulse width control module 414 usingbus 402. The pulse width control module 414 provides an enabling pulseof duration equal to the pulse width via a conductor 405. Pulses withthe selected characteristics are then delivered from stimulation device100 through cable 406 to stimulation element 150. Stimulation element150, typically comprising one or more electrodes as are describedhereabove, can be positioned to stimulate the fornix and/or otherregions of the brain or other body tissue. At the time that all or aportion of stimulation device 100 is implanted or otherwise positioned,a clinician can program certain key parameters into the memory 422 ofstimulation device 100, such as via telemetry from an externalcontroller, such as controller 200 described in reference to FIG. 1hereabove. These parameters can be updated subsequently as needed, suchas to modify one or more test or treatment stimulation parameters basedon diagnostic data produced by a diagnostic device (e.g. diagnostic data305 produced by diagnostic tool 300 of FIG. 1). Battery 411 can provideelectrical power to one or more components of stimulation device 100described herein.

Stimulation element 150 can comprise one or more deep brain stimulationelectrodes, such as electrodes model 3387 produced by Medtronic ofMinneapolis, Minn. These electrodes can be bilaterally implanted suchthat the tips of the electrodes are positioned in a region where cellscan be recorded during micro-recording mapping. Alternatively, a singleelectrode can be implanted unilaterally. Energy can be applied at afrequency of 2 Hz to 1000 Hz, such as at a frequency of approximately130 Hz. Energy can be delivered at a constant or varied pulse amplitude,such as at a constant pulse amplitude of approximately 500 μA. Energycan be delivered at a voltage between 0.1 and 10 Volts, such as between1 Volt and 6 Volts, such as at a voltage of approximately 3 Volts.Energy delivery can be given in a series of on and off times, such aswith an on-time of approximately 30 μseconds to 200 μseconds, such aswith an on time of approximately 90 μseconds. The duration of energydelivery can range from 30 minutes to 120 minutes, such as a duration ofapproximately 60 minutes, which can be repeated at regular or irregulartime intervals.

The embodiments of the present inventive concepts can be configured asopen-loop systems. The microcomputer algorithm programmed by theclinician sets the stimulation parameters of the stimulation device 100.In open-loop embodiments, this algorithm can change one or moreparameter values over time, but does so independent of any changes insymptoms or other physiologic changes the patient can be experiencing.Alternatively, a closed-loop system discussed below which incorporates asensor 430 to provide feedback can be used to provide enhanced results.Sensor 430 (e.g. an implanted or external sensor) can be used with aclosed loop feedback system in order to automatically orsemi-automatically determine the level of stimulation necessary toachieve the desired level of improved cognitive function and/or to avoidan adverse event. In closed-loop embodiments, microprocessor 410 canexecute an algorithm in order to provide stimulation with closed loopfeedback control. Such an algorithm can analyze a sensed signal fromsensor 430 and deliver stimulation therapy (e.g. delivery or electrical,magnetic, light, sound and/or chemical treatment therapy) based on thesensed signal. Adjustments can be made to one or more treatmentstimulation parameters when the signal falls within or outsidepredetermined values or windows, for example, predetermined levels ofBDNF and other neurotrophins (e.g., NGF, CNTF, FGF, EGF, NT-3) andcorticosteroids. Closed loop applications can be driven by diagnosticdata, such as diagnostic data 305 produced by diagnostic tool 300described in reference to FIG. 1 hereabove.

For example, in some embodiments, the patient can engage in a specifiedcognitive task, wherein the system measures one or more characteristicsto determine if the levels sensed by sensor 430 are at expectedthresholds. If one or more of the sensed characteristics are outside apredetermined threshold, the system can initiate and/or modify one ormore treatment stimulation parameters, such as to enhance or otherwiseimprove cognitive function.

In some embodiments, the system can be continuously providingclosed-loop feedback control. In other embodiments, the system canintermittently operate in closed-loop feedback control, such as based ona time of day (e.g., during hours that the patient is awake) or based ona cognitive task (e.g., when the patient is working). In yet otherembodiments, the system can be switchable between open-loop andclosed-loop by operator control, automatically and/or manually (e.g.manually via a handheld controller).

In some embodiments, stimulation therapy can be provided in relation tolearning a task. For example, electrical stimulation and/or drugdelivery can be applied before, after and/or during the performance of amemory, cognitive or motor task to facilitate the acquisition oflearning or consolidation of the task. In so doing, the rate of memoryacquisition and learning can be accelerated and enhanced in magnitude.For example, electrical stimulation and/or drug delivery can be providedbefore, during, and/or after periods when the patient is learning a newlanguage or playing a new instrument. Such therapy can be useful duringthe encoding, consolidation and/or retrieval phases of memory. Theneuromodulation intervention, brain stimulation or drug delivery canoccur before, after or simultaneously to the memory, cognitive of motorskill task.

In another aspect of the invention, stimulation therapy can be utilizedto enhance neurogenesis as a method of improving cognitive function.Techniques for enhancing neurogenesis through treatment therapy aredisclosed in U.S. Patents “Cognitive Function Within A Human Brain”,U.S. Ser. No. 11/303,293; “Inducing Neurogenesis Within A Human Brain”,U.S. Ser. No. 11/303,292; and “Regulation of Neurotrophins”, U.S. Ser.No. 11/303,619; as well as U.S. patent application “Method Of TreatingCognitive Disorders Using Neuromodulation”, U.S. Ser. No. 11/364,977;the contents of which are each incorporated herein by reference in theirentirety.

Referring back to FIG. 4, the system can optionally utilize closed-loopfeedback control having an analog to digital (A-to-D) converter 424coupled to sensor 430 via pathways 431 and 432. Output of the A-to-Dconverter 424 is connected to microprocessor 410 through peripheral bus402 including address, data and control lines. Microprocessor 410processes sensor 430 data in different ways depending on the type oftransducer in use and regulates delivery, via a control algorithm, ofstimulation based on the sensed signal. For example, when the signal onsensor 430 exceeds a level programmed by the clinician and stored in amemory 422, increasing amounts of stimulation can be applied through anoutput driver circuit 418. In the case of electrical stimulation, aparameter of the stimulation can be adjusted such as amplitude, pulsewidth and/or frequency.

Parameters which can be sensed include the activity of single neurons asdetected with microelectrode recording techniques, local fieldpotentials (LFPs), and event related potentials (ERPs), for example inresponse to a memory task or sensory stimulus and electroencephalogramor electrocorticogram. For example, U.S. Pat. No. 6,227,203 providesexamples of various types of sensors that can be used to detect asymptom or a condition of a cognitive disorder and responsively generatea neurological signal. In an embodiment, a neurochemical characteristicof the cognitive function can be sensed, additionally or alternatively.For example, sensing of local levels of neurotransmitters (e.g.glutamate, GABA, Aspartate), local pH or ion concentration, lactatelevels, local cerebral blood flow, glucose utilization or oxygenextraction can also be used as the input component of a closed loopsystem. These measures can be taken at rest or in response to a specificmemory or cognitive task or in response to a specific sensory or motorstimulus. In another embodiment, an electro-physiological characteristicof the cognitive function can be sensed by sensor 430. The informationcontained within the neuronal firing spike train, including spikeamplitude, frequency of action potentials, signal to noise ratio, thespatial and temporal features and the pattern of neuronal firing,oscillation behavior and inter-neuronal correlated activity can be usedto deliver therapies on a contingency basis in a closed loop system.Moreover, treatment therapy delivered can be immediate or delayed,diurnal, constant or intermittent depending on contingencies as definedby the closed loop system.

The foregoing description and accompanying drawings set forth a numberof examples of representative embodiments at the present time. Variousmodifications, additions and alternative designs will become apparent tothose skilled in the art in light of the foregoing teachings withoutdeparting from the spirit hereof, or exceeding the scope hereof, whichis indicated by the following claims rather than by the foregoingdescription. All changes and variations that fall within the meaning andrange of equivalency of the claims are to be embraced within theirscope.

1. (canceled)
 2. A method for treating a neurological disease ordisorder in a patient comprising: providing a stimulator, a controller,and diagnostic tool; implanting the stimulator in a target region of thepatient's brain; delivering test stimulation energy to the brain tissuethrough the stimulator to the target region of the patient's brain basedon the at least one test stimulation parameter; measuring at least onepatient parameter with the diagnostic tool in response to the teststimulation energy and producing diagnostic data representing said atleast one measured patient parameter; analyzing the diagnostic data andcomparing the diagnostic data to a threshold characteristic of anadverse event or a desired event with the controller; and deliveringtreatment stimulation energy to the patient's brain tissue based on theat least one treatment stimulation parameter.
 3. The method according toclaim 2, wherein the controller sets the at least one treatmentstimulation parameter based on a safety margin based on the comparisonof the diagnostic data to the threshold characteristic.
 4. The methodaccording to claim 2, wherein the neurological disease or neurologicaldisorder comprises Alzheimer's Disease.
 5. The method according to claim2, wherein the target region comprises a fornix.
 6. The method accordingto claim 2, wherein the at least one treatment stimulation parameter isselected to prevent or reduce the adverse event.
 7. The method accordingto claim 2, wherein the at least one treatment stimulation parameter isselected to improve treatment of the neurological disease or disorder.8. The method according to claim 2, wherein at least one of thestimulation parameter comprises a signal voltage ranging between 0.1Volts and 10.0 Volts.
 9. The method according to claim 2, wherein thecontroller sets at least one stimulation parameter based on a thresholdat which the adverse event is detected by the diagnostic tool.
 10. Themethod according to claim 9, wherein the adverse event comprises anevent selected from the group consisting of: undesirable heart rate;undesirable respiration rate; undesirable sweating; undesirablehallucinations; undesirable tingling; flushing; an undesirablepsychiatric effect; an undesirable cognitive effect; unpleasantgeneralized warming; undesirable perceptions described as deja vu;seizure; synchronized neuronal firing pattern; undesired neural responsetime; undesired brain state; undesired theta phase; undesired p300amplitude; and combinations thereof.
 11. The method according to claim9, wherein the at least one stimulation parameter is set using a safetymargin.
 12. The method according to claim 11, wherein the safety margincomprises at least a 10% safety margin.
 13. The method according toclaim 2, wherein the controller sets the at least one stimulationparameter based on a threshold at which a desired event was detected bythe diagnostic tool.
 14. The method according to claim 13, wherein thedesired event comprises an event selected from the group consisting of:recall of a desired memory; achievement of desired memory learning;desired level of neuronal activity; acceptable physiologic conditionsuch as an acceptable heart rate or acceptable level of neuronalactivity; experiential phenomena; and combinations thereof.
 15. Themethod according to claim 2, wherein the diagnostic tool detects theadverse event.
 16. The method according to claim 15, wherein the adverseevent comprises an event selected from the group consisting of:undesirable heart rate; undesirable respiration rate; undesirablesweating; undesirable hallucinations; undesirable tingling; flushing;undesirable psychiatric effect; undesirable cognitive effect; unpleasantgeneralized warming; undesirable perceptions described as deja vu;seizure; synchronized neuronal firing pattern; undesired neural responsetime; undesired brain state; undesired theta phase; undesired p300amplitude; and combinations thereof.
 17. The method according to claim2, wherein the diagnostic tool measuring at least one patient parametercomprises measuring at least one of heart rate; EKG; blood oxygen;combined heart rate and blood oxygen; blood pressure; neuronal activity;EEG; evoked response potential (ERP); neurochemical levels; andrespiration.